Tafazzin: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}{{Pfam_box|Symbol=TAZ|Name=Tafazzin|image=|width=|caption=|Pfam=|InterPro=IPR000872|SMART=|Prosite=|SCOP=|TCDB=|OPM family=|OPM protein=|PDB=|Membranome family=459}}'''Tafazzin''' is a [[protein]] that in humans is encoded by the ''TAZ'' [[gene]].<ref name="entrez5">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6901|title=Entrez Gene: tafazzin|access-date=}}{{PD-notice}}</ref> Tafazzin is highly expressed in [[Cardiac muscle|cardiac]] and [[skeletal muscle]], and functions as a [[phospholipid]]-[[lysophospholipid]] [[transacylase]] (it belongs to [[phospholipid:diacylglycerol acyltransferase]]s).<ref name="pmid197007665">{{cite journal | vauthors = Xu Y, Zhang S, Malhotra A, Edelman-Novemsky I, Ma J, Kruppa A, Cernicica C, Blais S, Neubert TA, Ren M, Schlame M | title = Characterization of tafazzin splice variants from humans and fruit flies | journal = The Journal of Biological Chemistry | volume = 284 | issue = 42 | pages = 29230–9 | date = October 2009 | pmid = 19700766 | pmc = 2781466 | doi = 10.1074/jbc.M109.016642 }}</ref><ref name="pmid170821945">{{cite journal | vauthors = Xu Y, Malhotra A, Ren M, Schlame M | title = The enzymatic function of tafazzin | journal = The Journal of Biological Chemistry | volume = 281 | issue = 51 | pages = 39217–24 | date = December 2006 | pmid = 17082194 | doi = 10.1074/jbc.M606100200 }}</ref> It catalyzes remodeling of immature [[cardiolipin]] to its mature composition containing a predominance of tetralinoleoyl moieties.<ref name="pmid210683805">{{cite journal | vauthors = Acehan D, Vaz F, Houtkooper RH, James J, Moore V, Tokunaga C, Kulik W, Wansapura J, Toth MJ, Strauss A, Khuchua Z | title = Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome | journal = The Journal of Biological Chemistry | volume = 286 | issue = 2 | pages = 899–908 | date = January 2011 | pmid = 21068380 | pmc = 3020775 | doi = 10.1074/jbc.M110.171439 }}</ref> Several different [[isoforms]] of the tafazzin protein are produced from the ''TAZ'' gene. A long form and a short form of each of these isoforms is produced; the short form lacks a [[hydrophobic]] leader sequence and may exist as a [[cytoplasm]]ic [[protein]] rather than being [[membrane-bound]]. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells.<ref name="GHR5">{{cite web|url=http://ghr.nlm.nih.gov/gene/TAZ|title=TAZ|website=Genetics Home Reference|publisher=NCBI}}{{PD-notice}}</ref><ref name="entrez5" /> Mutations in the ''TAZ'' gene have been associated with mitochondrial deficiency, [[Barth syndrome]], [[dilated cardiomyopathy]] (DCM), hypertrophic DCM, [[endocardial fibroelastosis]], left ventricular noncompaction (LVNC), [[breast cancer]], [[Papillary thyroid cancer|papillary thyroid carcinoma]], [[Non-small-cell lung carcinoma|non-small cell lung cancer]], [[glioma]], [[Stomach cancer|gastric cancer]], [[thyroid neoplasm]]s, and [[Colorectal cancer|rectal cancer]].<ref name="entrez5" /><ref name=":04">{{cite journal | vauthors = Huang W, Lv X, Liu C, Zha Z, Zhang H, Jiang Y, Xiong Y, Lei QY, Guan KL | title = The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition | journal = The Journal of Biological Chemistry | volume = 287 | issue = 31 | pages = 26245–53 | date = July 2012 | pmid = 22692215 | pmc = 3406709 | doi = 10.1074/jbc.M112.382036 }}</ref><ref name=":14">{{cite journal | vauthors = Ge L, Li DS, Chen F, Feng JD, Li B, Wang TJ | title = TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells | journal = International Journal of Oncology | volume = 51 | issue = 1 | pages = 307–315 | date = July 2017 | pmid = 28534974 | doi = 10.3892/ijo.2017.3998 }}</ref><ref name=":24">{{cite journal | vauthors = Chen M, Zhang Y, Zheng PS | title = Tafazzin (TAZ) promotes the tumorigenicity of cervical cancer cells and inhibits apoptosis | journal = PLOS One | volume = 12 | issue = 5 | pages = e0177171 | date = 2017 | pmid = 28489874 | pmc = 5425199 | doi = 10.1371/journal.pone.0177171 }}</ref>
'''Tafazzin''' is a [[protein]] that in humans is encoded by the ''TAZ'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: tafazzin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6901| accessdate = }}</ref> Tafazzin is highly expressed in [[cardiac muscle|cardiac]] and [[skeletal muscle]]. It is involved in the metabolism of [[cardiolipin]].<ref name="pmid19416660">{{cite journal |vauthors=Malhotra A, Xu Y, Ren M, Schlame M |title=Formation of molecular species of mitochondrial cardiolipin. 1. A novel transacylation mechanism to shuttle fatty acids between sn-1 and sn-2 positions of multiple phospholipid species |journal=Biochim. Biophys. Acta |volume=1791 |issue=4 |pages=314–20 |date=April 2009 |pmid=19416660 |pmc=2679859 |doi=10.1016/j.bbalip.2009.01.004 |url=http://linkinghub.elsevier.com/retrieve/pii/S1388-1981(09)00007-9}}</ref>


Tafazzin functions as a [[phospholipid]]-[[lysophospholipid]] [[transacylase]].<ref name="pmid19700766">{{cite journal |vauthors=Xu Y, Zhang S, Malhotra A, etal |title=Characterization of Tafazzin Splice Variants from Humans and Fruit Flies |journal=J. Biol. Chem. |volume=284 |issue=42 |pages=29230–9 |date=October 2009 |pmid=19700766 |pmc=2781466 |doi=10.1074/jbc.M109.016642 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=19700766}}</ref><ref name="pmid17082194">{{cite journal |vauthors=Xu Y, Malhotra A, Ren M, Schlame M |title=The enzymatic function of tafazzin |journal=J. Biol. Chem. |volume=281 |issue=51 |pages=39217–24 |date=December 2006 |pmid=17082194 |doi=10.1074/jbc.M606100200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=17082194}}</ref>
== Structure ==
The ''TAZ'' gene is located on the [[Locus (genetics)|q arm]] of [[chromosome X]] at position 28 and it spans 10,208 base pairs.<ref name="entrez5" /> The ''TAZ'' gene produces a 21.3 kDa protein composed of 184 [[amino acids]].<ref name="COPaKB5">{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB5">{{cite web |url=https://amino.heartproteome.org/web/protein/C9J699 |title=TAZ Tafazzin|website=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)}}</ref> The structure of the encoded protein has been found to differ at their [[N terminus]] and the central region, which are two functionally notable regions. A 30 residue [[hydrophobic]] stretch at the [[N terminus]] may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between [[amino acids]] 124 and 195 in the central region. This [[hydrophilic]] region is known to interact with other proteins. TAZ has no known resemblance to other proteins.<ref name="pmid86304915">{{cite journal | vauthors = Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D | title = A novel X-linked gene, G4.5. is responsible for Barth syndrome | journal = Nature Genetics | volume = 12 | issue = 4 | pages = 385–9 | date = April 1996 | pmid = 8630491 | doi = 10.1038/ng0496-385 }}</ref>
 
Tafazzin is encoded by the TAZ gene. It is very unfortunate that a protein called TAZ (a 50kDA protein) which is a part of the Hippo/YAP/TAZ pathway gets confused with Tafazzin due to this misnaming often.
 
Tafazzin  has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression.
 
== Function ==
The ''TAZ'' gene provides instructions for producing a protein called tafazzin, which is located in structures called [[mitochondria]], which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin (CL), which plays critical roles in the mitochondrial inner membrane.<ref name="GHR5" />
 
===Transacylase (remodeling)===
After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. The remodeling process of cardiolipin involves reaching a final acyl composition. TAZ interacts with an immature [[cardiolipin]] by adding a fatty acid called [[linoleic acid]], which [[Catalysis|catalyzes]] the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle begins with a deacylation mediated by a phospholipase and ends which forms monolyso-CL (MLCL). The cycle ends with a CoA-dependent reacylation. In contrast, transacylation involves the transfer of a [[linoleic acid]] (LA) group from [[phosphatidylcholine]] (PC) to MLCL. Such enzymatic activity forms lyso-PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl-containing PC. Such remodeling processes converts [[cardiolipin]] into a mature composition that contains a predominance of tetralinoleoyl moieties. The process enables the proper function of [[cardiolipin]].<ref name="pmid210683805" /><ref name="GHR5" /><ref name = "CL">{{cite journal | vauthors = Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Pérez-Cerdá C, Morrone A, Malvagia S, Wanders RJ, Kulik W, Vaz FM | title = The enigmatic role of tafazzin in cardiolipin metabolism | journal = Biochimica et Biophysica Acta | volume = 1788 | issue = 10 | pages = 2003–14 | date = October 2009 | pmid = 19619503 | doi = 10.1016/j.bbamem.2009.07.009 }}</ref>
 
===Cardiolipin in mitochondrial structure and function===
[[Cardiolipin]] is a complex [[glycerophospholipid]] which contains 4 [[Acyl|acyl groups]] linked to three glycerol moietie localized in the [[mitochondrial inner membrane]]. These acyl groups include [[oleic acid]] and [[linoleic acid]]. Due to this composition, cardiolipin exhibits a conical structure, which allows for membrane curvature called [[cristae]]. Such qualities allow CL to play essential roles in maintaining mitochondrial shape, energy production, and protein transport within cells.<ref name="GHR5" />
During [[apoptosis]] and similar processes, CL is known to act as a platform for proteins and other machinery involved.
 
===Influence of cardiolipin on the respiratory chain===
Cardiolipin has been shown to assist in energy production of the [[mitochondria]]. Several proteins in the mitochondrial respiratory chain require CL for optimal function.<ref>{{cite journal | vauthors = Houtkooper RH, Vaz FM | title = Cardiolipin, the heart of mitochondrial metabolism | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 16 | pages = 2493–506 | date = August 2008 | pmid = 18425414 | doi = 10.1007/s00018-008-8030-5 }}</ref>
CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient [[electron transport]].<ref>{{cite journal | vauthors = Brandner K, Mick DU, Frazier AE, Taylor RD, Meisinger C, Rehling P | title = Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth Syndrome | journal = Molecular Biology of the Cell | volume = 16 | issue = 11 | pages = 5202–14 | date = November 2005 | pmid = 16135531 | pmc = 1266419 | doi = 10.1091/mbc.e05-03-0256 }}</ref> CL assists in forming super-complexes with proteins localized in the inner mitochondrial matrix, which include the ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III,IV, V).<ref>{{cite journal |last1=Barth |first1=PG |last2=Valianpour |first2=F |last3=Bowen |first3=VM |last4=Lam |first4=J |last5=Duran |first5=M |last6=Vaz |first6=FM |last7=Wanders |first7=RJ |title=X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. |journal=American Journal of Medical Genetics Part A |date=1 May 2004 |volume=126A |issue=4 |pages=349–54 |doi=10.1002/ajmg.a.20660 |pmid=15098233}}</ref><ref>{{cite journal | vauthors = Hoffmann B, Stöckl A, Schlame M, Beyer K, Klingenberg M | title = The reconstituted ADP/ATP carrier activity has an absolute requirement for cardiolipin as shown in cysteine mutants | journal = The Journal of Biological Chemistry | volume = 269 | issue = 3 | pages = 1940–4 | date = January 1994 | pmid = 8294444 }}</ref> CL also enables trapping of protons in the [[intermembrane space]], aiding [[ATP synthase]] to carry out its function of channeling protons into the mitochondrial matrix.<ref name = "CL" />
 
 
==Clinical significance==
Mutations in the ''TAZ'' gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC).<ref name="entrez5" /> TAZ has also been associated with various cancers, including [[breast cancer]], [[Papillary thyroid cancer|papillary thyroid carcinoma]] and [[Non-small-cell lung carcinoma|non-small cell lung cancer]], [[glioma]], [[Stomach cancer|gastric cancer]], [[thyroid neoplasm]]s, and [[Colorectal cancer|rectal cancer]].<ref name=":04" /><ref name=":14" /><ref name=":24" />
 
===Barth Syndrome===
[[Barth syndrome]] is an X-linked disease caused by mutations in the ''TAZ'' gene.<ref name="uniprot5">{{Cite web|url=https://www.uniprot.org/uniprot/Q16635|title=TAZ - Tafazzin - Homo sapiens (Human) - TAZ gene & protein|access-date=2018-08-24}}</ref><ref name="uniprot05">{{cite journal | vauthors =  | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref> More than 160 mutations in the TAZ gene have been found to this disease. It is a rare condition that occurs almost exclusively in males. TAZ gene mutations that cause barth syndrome result in the production of tafazzin proteins with little or no function. As a result, [[linoleic acid]] is not added to [[cardiolipin]], which causes problems with normal mitochondrial shape and functions such as energy production and protein transport. [[Tissue (biology)|Tissues]] with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria. Additionally, affected [[white blood cells]] have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened [[immune system]] and recurrent [[infections]]. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome.<ref name="GHR5" />
 
Common clinical manifestations include:<ref name="GHR5" /><ref name="uniprot5" /><ref name="uniprot05" />
 
* dilated [[cardiomyopathy]] (enlarged and weakened heart)
* [[muscle weakness]]
* recurrent [[infections]]
* [[short stature]]
* [[endocardial fibroelastosis]]
* [[growth retardation]]
* [[neutropenia]]
* organic [[aciduria]] ([[3-methylglutaconic acid]])
 
Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.<ref name="uniprot5" /><ref name="uniprot05" />
 
A c.348C>T mutation resulted in dilated [[cardiomyopathy]] with noncompaction of the [[Ventricle (heart)|ventricular]] myocardium.<ref name="pmid268532235">{{cite journal | vauthors = Ferri L, Dionisi-Vici C, Taurisano R, Vaz FM, Guerrini R, Morrone A | title = When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription | journal = Clinical Genetics | volume = 90 | issue = 5 | pages = 461–465 | date = November 2016 | pmid = 26853223 | doi = 10.1111/cge.12756 }}</ref> A frame shift mutation of c.227delC displayed symptoms of [[neutropenia]], [[cardiomegaly]], and other common symptoms of Bath Syndrome.<ref name="pmid236782745">{{cite journal | vauthors = Kim GB, Kwon BS, Bae EJ, Noh CI, Seong MW, Park SS | title = A novel mutation of the TAZ gene in Barth syndrome: acute exacerbation after contrast-dye injection | journal = Journal of Korean Medical Science | volume = 28 | issue = 5 | pages = 784–7 | date = May 2013 | pmid = 23678274 | pmc = 3653095 | doi = 10.3346/jkms.2013.28.5.784 }}</ref> Another a c.C153G mutation resulted in severe metabolic [[acidosis]], [[cardiomegaly]], and other major symptoms of [[Barth syndrome]].<ref name="pmid178467865">{{cite journal | vauthors = Yen TY, Hwu WL, Chien YH, Wu MH, Lin MT, Tsao LY, Hsieh WS, Lee NC | title = Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review | journal = European Journal of Pediatrics | volume = 167 | issue = 8 | pages = 941–4 | date = August 2008 | pmid = 17846786 | doi = 10.1007/s00431-007-0592-y }}</ref>
 
In conclusion, tafazzin is responsible for remodeling of a phospholipid [[cardiolipin]] (CL),<ref name="pmid92595715">{{cite journal | vauthors = Neuwald AF | title = Barth syndrome may be due to an acyltransferase deficiency | journal = Current Biology | volume = 7 | issue = 8 | pages = R465–6 | date = August 1997 | pmid = 9259571 | doi = 10.1016/S0960-9822(06)00237-5 }}</ref> the signature lipid of the mitochondrial inner membrane. Therefore, a dysfunctioning tafazzin has been found to lead to an impaired [[mitochondrial respiratory chain]]. As a result, Barth syndrome patients exhibit defects in [[cardiolipin]] metabolism, including aberrant [[cardiolipin]] fatty acyl composition, accumulation of [[monolysocardiolipin]] (MLCL) and reduced total [[cardiolipin]] levels.<ref name="pmid104077875">{{cite journal | vauthors = Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, Baas F | title = X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060) | journal = Journal of Inherited Metabolic Disease | volume = 22 | issue = 4 | pages = 555–67 | date = June 1999 | pmid = 10407787 | doi = 10.1023/A:1005568609936 }}</ref><ref name="pmid158055425">{{cite journal | vauthors = Valianpour F, Mitsakos V, Schlemmer D, Towbin JA, Taylor JM, Ekert PG, Thorburn DR, Munnich A, Wanders RJ, Barth PG, Vaz FM | title = Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis | journal = Journal of Lipid Research | volume = 46 | issue = 6 | pages = 1182–95 | date = June 2005 | pmid = 15805542 | doi = 10.1194/jlr.M500056-JLR200 }}</ref> This may lead to acute [[Metabolism|metabolic decompensation]] and sudden death. [[Cardiac transplantation]] is the only possibility at the present time.<ref name="pmid178467865" />
 
===Dilated cardiomyopathy (DCM)===
Some mutations in the ''TAZ'' gene cause dilated [[cardiomyopathy]] without the other features of [[Barth syndrome]]. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently, often resulting in [[heart failure]]. The decreased blood flow can lead to swelling in the legs and [[abdomen]], fluid in the lungs, and an increased risk of [[blood clots]].<ref name="GHR5" />
 
===Isolated noncompaction of left ventricular myocardium (INVM)===
Mutations in the ''TAZ'' gene can cause a heart condition called isolated noncompaction of left ventricular myocardium (INVM). This condition occurs when the lower left chamber of the heart ([[Ventricle (heart)|left ventricle]]) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently. Abnormal heart rhythms ([[arrhythmias]]) can also occur. INVM frequently causes heart failure.<ref name="GHR5" />
 
=== Cancer ===
Highly elevated TAZ activity has been linked to [[Carcinogenesis|tumorigenesis]] and [[Carcinogenesis|oncogenic]] activity. It has also been associated with and various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, and glioma.<ref name=":04" /> In breast cancer, TAZ has been shown to be required for cancer cells to sustain self-renewal and create tumors.<ref>{{cite journal | vauthors = Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S | title = The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells | journal = Cell | volume = 147 | issue = 4 | pages = 759–72 | date = November 2011 | pmid = 22078877 | doi = 10.1016/j.cell.2011.09.048 }}</ref> Additionally, TAZ has been found to be highly expressed in gastric cancer cells resistant to [[cisplatin]]. This resistance was identified to be due to the acquired ability of the cancer cells to undergo [[Epithelial–mesenchymal transition|epithelial-mesenchymal transition]] (EMT). The findings that TAZ is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer.<ref name=":04" /><ref name=":14" /> High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit [[apoptosis]].<ref name=":24" /> In a study of 140 Swedish rectal cancer patients, high levels of TAZ was linked to rectal cancer development. Additionally, the levels of TAZ were connected to the radiotherapy response of the patients, potentially offering insight into cancer recurrence in patients.<ref>{{cite journal | vauthors = Pathak S, Meng WJ, Zhang H, Gnosa S, Nandy SK, Adell G, Holmlund B, Sun XF | title = Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy | journal = PLOS One | volume = 9 | issue = 5 | pages = e98317 | date = 2014 | pmid = 24858921 | pmc = 4032294 | doi = 10.1371/journal.pone.0098317 }}</ref> A potential link between PI3K and TAZ indicates a possible association between PI3K signaling and TAZ as both were highly elevated in [[PTEN (gene)|PTEN]] mutant cancer cells.<ref name=":04" />
 
== Interactions ==
TAZ has been shown to have [[protein-protein interactions]] with the following and more.<ref name="hi225">{{cite journal | vauthors = Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P | title = MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation | journal = Cell | volume = 151 | issue = 7 | pages = 1528–41 | date = December 2012 | pmid = 23260140 | doi = 10.1016/j.cell.2012.11.053 }}</ref><ref name="uniprot5" />
 
* [[FUT11]]
* [[BTRC (gene)|BTRC]]
* [[NAGA]]
* [[NID2]]
* [[ANKRD46]]
* [[VWDE]]
* [[ITGA8]]


==Pathology==
The mutation of the tafazzin gene is associated with a number of clinical disorders including [[Barth syndrome (BTHS)]] (type II [[3-Methylglutaconic aciduria]]), [[dilated cardiomyopathy| dilated cardiomyopathy (DCM)]], hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). Tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL),<ref name="pmid9259571">{{cite journal | author = Neuwald AF | title = Barth syndrome may be due to an acyltransferase deficiency | journal = Curr. Biol. | volume = 7 | issue = 8 | pages = R465–6 |date=August 1997 | pmid = 9259571 | doi =10.1016/S0960-9822(06)00237-5 | url =  }}</ref> the signature lipid of the mitochondrial inner membrane. As a result, BTHS patients exhibit defects in CL metabolism, including aberrant CL fatty acyl composition, accumulation of [[monolysocardiolipin]] (MLCL) and reduced total CL levels.<ref name="pmid10407787">{{cite journal |vauthors=Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, Baas F | title = X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060) | journal = J. Inherit. Metab. Dis. | volume = 22 | issue = 4 | pages = 555–67 |date=June 1999 | pmid = 10407787 | doi = 10.1023/A:1005568609936| url =  }}</ref><ref name="pmid15805542">{{cite journal |vauthors=Valianpour F, Mitsakos V, Schlemmer D, Towbin JA, Taylor JM, Ekert PG, Thorburn DR, Munnich A, Wanders RJ, Barth PG, Vaz FM | title = Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis | journal = J. Lipid Res. | volume = 46 | issue = 6 | pages = 1182–95 |date=June 2005 | pmid = 15805542 | doi = 10.1194/jlr.M500056-JLR200 | url =  }}</ref>


==History==
==History==
The protein was identified by [[Italy|Italian]] scientists Silvia Bione ''et al.'' in 1996.<ref name="pmid8630491">{{cite journal |vauthors=Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D | title = A novel X-linked gene, G4.5. is responsible for Barth syndrome | journal = Nat. Genet. | volume = 12 | issue = 4 | pages = 385–9 |date=April 1996 | pmid = 8630491 | doi = 10.1038/ng0496-385 | url =  }}</ref> Owing to the complex procedure required for the identification of ''tafazzin'', the protein was named after "[[Tafazzi]]", a masochistic comic character in an Italian television show.
The protein was identified by [[Italy|Italian]] scientists Silvia Bione ''et al.'' in 1996.<ref name="pmid86304915" /> Owing to the complex procedure required for the identification of ''tafazzin'', the protein was named after "[[Tafazzi]]", a masochistic comic character in an Italian television show.


==References==
== References ==
{{reflist|2}}
{{Reflist|32em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|32em}}
*{{cite journal   |vauthors=Acehan D, Vaz F, Houtkooper RH, etal |title=Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome  |journal=J Biol Chem |year= 2011 Jan 14;286(2):899–908. |pmid= 21068380 |volume=286  |issue=2  |pages=899–908  |doi=10.1074/jbc.M110.171439  |pmc=3020775}}
* {{cite journal|date=Dec 9, 2010|title=Mouse model of Barth syndrome|url=http://www.nature.com/search/executeSearch?sp-q-1=scibx&sp-q=Mouse+model+of+Barth+syndrome&sp-c=25&sp-m=0&sp-s=date_descending&include-collections=journals_nature%2Ccrawled_content&exclude-collections=journals_palgrave%2Clab_animal&sp-a=sp1001702d&sp-sfvl-|journal=SciBX|volume=3|issue=47|pages=1427|doi=10.1038/scibx.2010.1427}}
*{{cite journal |title=Mouse model of Barth syndrome  |journal= SciBX |volume=3 |date= Dec 9, 2010 |doi=10.1038/scibx.2010.1427 |url=http://www.nature.com/search/executeSearch?sp-q-1=scibx&sp-q=Mouse+model+of+Barth+syndrome&sp-c=25&sp-m=0&sp-s=date_descending&include-collections=journals_nature%2Ccrawled_content&exclude-collections=journals_palgrave%2Clab_animal&sp-a=sp1001702d&sp-sfvl-  |issue=47}}
* {{cite journal | vauthors = Soustek MS, Falk DJ, Mah CS, Toth MJ, Schlame M, Lewin AS, Byrne BJ | title = Characterization of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency | journal = Human Gene Therapy | volume = 22 | issue = 7 | pages = 865–71 | date = July 2011 | pmid = 21091282 | pmc = 3166794 | doi = 10.1089/hum.2010.199 }}
*{{cite journal   |vauthors=Soustek MS, Falk D, Mah C, Toth M, Schlame M, etal |title=Characterization of a Transgenic Short Hairpin RNA-Induced Murine Model of Tafazzin Deficiency  |journal=Hum Gene Ther. |year= 2011 |pmid= 21091282 |volume=22  |issue=7  |pages=865–71  |doi=10.1089/hum.2010.199  |pmc=3166794}}
* {{cite journal | vauthors = Takeda A, Sudo A, Yamada M, Yamazawa H, Izumi G, Nishino I, Ariga T | title = Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium | journal = European Journal of Pediatrics | volume = 170 | issue = 11 | pages = 1481–4 | date = November 2011 | pmid = 21932011 | doi = 10.1007/s00431-011-1576-5 }}
*{{cite journal   |vauthors=Takeda A, Sudo A, Yamada M, Yamazawa H, etal |title=Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium  |journal=Eur J Pediatr |year= 2011 Sep 20.|pmid= 21932011  |doi=10.1007/s00431-011-1576-5 |volume=170 |issue=11 |pages=1481–4}}
* {{cite journal | vauthors = Bachou T, Giannakopoulos A, Trapali C, Vazeou A, Kattamis A | title = A novel mutation in the G4.5 (TAZ) gene in a Greek patient with Barth syndrome | journal = Blood Cells, Molecules & Diseases | volume = 42 | issue = 3 | pages = 262–4 | year = 2009 | pmid = 19261493 | doi = 10.1016/j.bcmd.2008.11.004 }}
*{{cite journal   |vauthors=Bachou T, Giannakopoulos A, Trapali C, etal |title=A novel mutation in the G4.5 (TAZ) gene in a Greek patient with Barth syndrome |journal=Blood Cells Mol. Dis. |volume=42 |issue= 3 |pages= 262–4 |year= 2009|pmid= 19261493 |doi= 10.1016/j.bcmd.2008.11.004 }}
* {{cite journal | vauthors = Gonzalez IL | title = Barth syndrome: TAZ gene mutations, mRNAs, and evolution | journal = American Journal of Medical Genetics Part A | volume = 134 | issue = 4 | pages = 409–14 | date = May 2005 | pmid = 15793838 | doi = 10.1002/ajmg.a.30661 }}
*{{cite journal |author=Gonzalez IL |title=Barth syndrome: TAZ gene mutations, mRNAs, and evolution |journal=Am. J. Med. Genet. A |volume=134 |issue= 4 |pages= 409–14 |year= 2005 |pmid= 15793838 |doi= 10.1002/ajmg.a.30661 }}
* {{cite journal | vauthors = Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE | title = A human protein-protein interaction network: a resource for annotating the proteome | journal = Cell | volume = 122 | issue = 6 | pages = 957–68 | date = September 2005 | pmid = 16169070 | doi = 10.1016/j.cell.2005.08.029 }}
*{{cite journal   |vauthors=Stelzl U, Worm U, Lalowski M, etal |title=A human protein-protein interaction network: a resource for annotating the proteome |journal=Cell |volume=122 |issue= 6 |pages= 957–68 |year= 2005 |pmid= 16169070 |doi= 10.1016/j.cell.2005.08.029 }}
* {{cite journal | vauthors = Zimmerman RS, Cox S, Lakdawala NK, Cirino A, Mancini-DiNardo D, Clark E, Leon A, Duffy E, White E, Baxter S, Alaamery M, Farwell L, Weiss S, Seidman CE, Seidman JG, Ho CY, Rehm HL, Funke BH | title = A novel custom resequencing array for dilated  cardiomyopathy | journal = Genetics in Medicine | volume = 12 | issue = 5 | pages = 268–78 | date = May 2010 | pmid = 20474083 | pmc = 3018746 | doi = 10.1097/GIM.0b013e3181d6f7c0 }}
*{{cite journal   |vauthors=Barth PG, Valianpour F, Bowen VM, etal |title=X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update |journal=Am. J. Med. Genet. A |volume=126A |issue= 4 |pages= 349–54 |year= 2004 |pmid= 15098233 |doi= 10.1002/ajmg.a.20660 }}
* {{cite journal | vauthors = Malhotra A, Edelman-Novemsky I, Xu Y, Plesken H, Ma J, Schlame M, Ren M | title = Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 7 | pages = 2337–41 | date = February 2009 | pmid = 19164547 | pmc = 2650157 | doi = 10.1073/pnas.0811224106 }}
*{{cite journal   |vauthors=Zimmerman RS, Cox S, Lakdawala NK, etal |title=A novel custom resequencing array for dilated cardiomyopathy |journal=Genet. Med. |volume=12 |issue= 5 |pages= 268–78 |year= 2010 |pmid= 20474083 |doi=10.1097/GIM.0b013e3181d6f7c0  |pmc=3018746  }}
* {{cite journal | vauthors = van Werkhoven MA, Thorburn DR, Gedeon AK, Pitt JJ | title = Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth Syndrome | journal = Journal of Lipid Research | volume = 47 | issue = 10 | pages = 2346–51 | date = October 2006 | pmid = 16873891 | doi = 10.1194/jlr.D600024-JLR200 }}
*{{cite journal   |vauthors=Malhotra A, Edelman-Novemsky I, Xu Y, etal |title=Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=106 |issue= 7 |pages= 2337–41 |year= 2009 |pmid= 19164547 |doi= 10.1073/pnas.0811224106 |pmc=2650157}}
* {{cite journal | vauthors = Acehan D, Xu Y, Stokes DL, Schlame M | title = Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 87 | issue = 1 | pages = 40–8 | date = January 2007 | pmid = 17043667 | pmc = 2215767 | doi = 10.1038/labinvest.3700480 }}
*{{cite journal |vauthors=van Werkhoven MA, Thorburn DR, Gedeon AK, Pitt JJ |title=Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth Syndrome |journal=J. Lipid Res. |volume=47 |issue= 10 |pages= 2346–51 |year= 2006 |pmid= 16873891 |doi= 10.1194/jlr.D600024-JLR200 }}
* {{cite journal | vauthors = Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, Baas F | title = X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060) | journal = Journal of Inherited Metabolic Disease | volume = 22 | issue = 4 | pages = 555–67 | date = June 1999 | pmid = 10407787 | doi = 10.1023/A:1005568609936 }}
*{{cite journal |vauthors=Acehan D, Xu Y, Stokes DL, Schlame M |title=Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography |journal=Lab. Invest. |volume=87 |issue= 1 |pages= 40–8 |year= 2007 |pmid= 17043667 |doi= 10.1038/labinvest.3700480  |pmc=2215767 }}
* {{cite journal | vauthors = Claypool SM, Boontheung P, McCaffery JM, Loo JA, Koehler CM | title = The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome | journal = Molecular Biology of the Cell | volume = 19 | issue = 12 | pages = 5143–55 | date = December 2008 | pmid = 18799610 | pmc = 2592642 | doi = 10.1091/mbc.E08-09-0896 }}
*{{cite journal   |vauthors=Barth PG, Wanders RJ, Vreken P, etal |title=X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060) |journal=J. Inherit. Metab. Dis. |volume=22 |issue= 4 |pages= 555–67 |year= 1999 |pmid= 10407787 |doi=10.1023/A:1005568609936  }}
* {{cite journal | vauthors = Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415–8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
*{{cite journal   |vauthors=Claypool SM, Boontheung P, McCaffery JM, etal |title=The Cardiolipin Transacylase, Tafazzin, Associates with Two Distinct Respiratory Components Providing Insight into Barth Syndrome |journal=Mol. Biol. Cell |volume=19 |issue= 12 |pages= 5143–55 |year= 2008 |pmid= 18799610 |doi= 10.1091/mbc.E08-09-0896 |pmc=2592642}}
* {{cite journal | vauthors = McKenzie M, Lazarou M, Thorburn DR, Ryan MT | title = Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients | journal = Journal of Molecular Biology | volume = 361 | issue = 3 | pages = 462–9 | date = August 2006 | pmid = 16857210 | doi = 10.1016/j.jmb.2006.06.057 | citeseerx = 10.1.1.314.3366 }}
*{{cite journal   |vauthors=Mehrle A, Rosenfelder H, Schupp I, etal |title=The LIFEdb database in 2006 |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415–8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 |pmc=1347501}}
* {{cite journal | vauthors = Lu B, Kelher MR, Lee DP, Lewin TM, Coleman RA, Choy PC, Hatch GM | title = Complex expression pattern of the Barth syndrome gene product tafazzin in human cell lines and murine tissues | journal = Biochemistry and Cell Biology | volume = 82 | issue = 5 | pages = 569–76 | date = October 2004 | pmid = 15499385 | doi = 10.1139/o04-055 }}
*{{cite journal |vauthors=McKenzie M, Lazarou M, Thorburn DR, Ryan MT |title=Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients |journal=J. Mol. Biol. |volume=361 |issue= 3 |pages= 462–9 |year= 2006 |pmid= 16857210 |doi= 10.1016/j.jmb.2006.06.057 }}
* {{cite journal | vauthors = Ma L, Vaz FM, Gu Z, Wanders RJ, Greenberg ML | title = The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome | journal = The Journal of Biological Chemistry | volume = 279 | issue = 43 | pages = 44394–9 | date = October 2004 | pmid = 15304507 | doi = 10.1074/jbc.M405479200 }}
*{{cite journal   |vauthors=Lu B, Kelher MR, Lee DP, etal |title=Complex expression pattern of the Barth syndrome gene product tafazzin in human cell lines and murine tissues |journal=Biochem. Cell Biol. |volume=82 |issue= 5 |pages= 569–76 |year= 2004 |pmid= 15499385 |doi= 10.1139/o04-055 }}
* {{cite journal | vauthors = Xu Y, Zhang S, Malhotra A, Edelman-Novemsky I, Ma J, Kruppa A, Cernicica C, Blais S, Neubert TA, Ren M, Schlame M | title = Characterization of tafazzin splice variants from humans and fruit flies | journal = The Journal of Biological Chemistry | volume = 284 | issue = 42 | pages = 29230–9 | date = October 2009 | pmid = 19700766 | pmc = 2781466 | doi = 10.1074/jbc.M109.016642 }}
*{{cite journal   |vauthors=Ma L, Vaz FM, Gu Z, etal |title=The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome |journal=J. Biol. Chem. |volume=279 |issue= 43 |pages= 44394–9 |year= 2004 |pmid= 15304507 |doi= 10.1074/jbc.M405479200 }}
* {{cite journal | vauthors = Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Pérez-Cerdá C, Morrone A, Malvagia S, Wanders RJ, Kulik W, Vaz FM | title = The enigmatic role of tafazzin in cardiolipin metabolism | journal = Biochimica et Biophysica Acta | volume = 1788 | issue = 10 | pages = 2003–14 | date = October 2009 | pmid = 19619503 | doi = 10.1016/j.bbamem.2009.07.009 }}
*{{cite journal   |vauthors=Xu Y, Zhang S, Malhotra A, etal |title=Characterization of Tafazzin Splice Variants from Humans and Fruit Flies |journal=J. Biol. Chem. |volume=284 |issue= 42 |pages= 29230–9 |year= 2009 |pmid= 19700766 |doi= 10.1074/jbc.M109.016642 |pmc=2781466}}
* {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
*{{cite journal   |vauthors=Houtkooper RH, Turkenburg M, Poll-The BT, etal |title=The enigmatic role of tafazzin in cardiolipin metabolism |journal=Biochim. Biophys. Acta |volume=1788 |issue= 10 |pages= 2003–14 |year= 2009 |pmid= 19619503 |doi= 10.1016/j.bbamem.2009.07.009 }}
* {{cite journal | vauthors = Saunders MA, Slatkin M, Garner C, Hammer MF, Nachman MW | title = The extent of linkage disequilibrium caused by selection on G6PD in humans | journal = Genetics | volume = 171 | issue = 3 | pages = 1219–29 | date = November 2005 | pmid = 16020776 | pmc = 1456824 | doi = 10.1534/genetics.105.048140 }}
*{{cite journal   |vauthors=Wiemann S, Arlt D, Huber W, etal |title=From ORFeome to Biology: A Functional Genomics Pipeline |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136–44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 |pmc=528930}}
* {{cite journal | vauthors = Vaz FM, Houtkooper RH, Valianpour F, Barth PG, Wanders RJ | title = Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism | journal = The Journal of Biological Chemistry | volume = 278 | issue = 44 | pages = 43089–94 | date = October 2003 | pmid = 12930833 | doi = 10.1074/jbc.M305956200 }}
*{{cite journal  |vauthors=Saunders MA, Slatkin M, Garner C, etal |title=The Extent of Linkage Disequilibrium Caused by Selection on G6PD in Humans |journal=Genetics |volume=171 |issue= 3 |pages= 1219–29 |year= 2005 |pmid= 16020776 |doi= 10.1534/genetics.105.048140  |pmc=1456824 }}
*{{cite journal  |vauthors=Vaz FM, Houtkooper RH, Valianpour F, etal |title=Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism |journal=J. Biol. Chem. |volume=278 |issue= 44 |pages= 43089–94 |year= 2003 |pmid= 12930833 |doi= 10.1074/jbc.M305956200 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1309/ GeneReviews/NCBI/NIH/UW entry on Dilated Cardiomyopathy Overview]
 
* [https://www.ncbi.nlm.nih.gov/books/NBK1309/ GeneReviews/NCBI/NIH/UW entry on Dilated Cardiomyopathy Overview]
* {{MeshName|TAZ+protein,+human}}
* {{MeshName|TAZ+protein,+human}}
 
{{Acyltransferases}}{{Phospholipid metabolism}}{{Portal bar|Mitochondria|Gene Wiki|border=no}}{{NLM content}}
{{Acyltransferases}}
{{Phospholipid metabolism}}


[[Category:Molecular biology]]
[[Category:Molecular biology]]
[[Category:Proteins]]
[[Category:Proteins]]
[[Category:Genetics]]
[[Category:Genetics]]

Latest revision as of 01:05, 25 December 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Tafazzin
Identifiers
SymbolTAZ
InterProIPR000872
Membranome459

Tafazzin is a protein that in humans is encoded by the TAZ gene.[1] Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases).[2][3] It catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties.[4] Several different isoforms of the tafazzin protein are produced from the TAZ gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells.[5][1] Mutations in the TAZ gene have been associated with mitochondrial deficiency, Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, left ventricular noncompaction (LVNC), breast cancer, papillary thyroid carcinoma, non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[1][6][7][8]

Structure

The TAZ gene is located on the q arm of chromosome X at position 28 and it spans 10,208 base pairs.[1] The TAZ gene produces a 21.3 kDa protein composed of 184 amino acids.[9][10] The structure of the encoded protein has been found to differ at their N terminus and the central region, which are two functionally notable regions. A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins. The second region is a variable exposed loop located between amino acids 124 and 195 in the central region. This hydrophilic region is known to interact with other proteins. TAZ has no known resemblance to other proteins.[11]

Tafazzin is encoded by the TAZ gene. It is very unfortunate that a protein called TAZ (a 50kDA protein) which is a part of the Hippo/YAP/TAZ pathway gets confused with Tafazzin due to this misnaming often.

Tafazzin has at least 4 different isoforms. It has a molecular weight around 35kDa but may also appear in lower molecular weights due to species differences in isoform expression.

Function

The TAZ gene provides instructions for producing a protein called tafazzin, which is located in structures called mitochondria, which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin (CL), which plays critical roles in the mitochondrial inner membrane.[5]

Transacylase (remodeling)

After its synthesis, cardiolipin cannot exert its proper functions until it is actively remodeled. The remodeling process of cardiolipin involves reaching a final acyl composition. TAZ interacts with an immature cardiolipin by adding a fatty acid called linoleic acid, which catalyzes the remodeling of the cardiolipin. The remodeling is achieved by transacylation or the deacylation-reacylation cycle. The deacylation-reacylation cycle, also known as the Lands cycle begins with a deacylation mediated by a phospholipase and ends which forms monolyso-CL (MLCL). The cycle ends with a CoA-dependent reacylation. In contrast, transacylation involves the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to MLCL. Such enzymatic activity forms lyso-PC and CL, and enriches the specific acyl chain of cardiolipin. The process has been shown to be specific for linoleoyl-containing PC. Such remodeling processes converts cardiolipin into a mature composition that contains a predominance of tetralinoleoyl moieties. The process enables the proper function of cardiolipin.[4][5][12]

Cardiolipin in mitochondrial structure and function

Cardiolipin is a complex glycerophospholipid which contains 4 acyl groups linked to three glycerol moietie localized in the mitochondrial inner membrane. These acyl groups include oleic acid and linoleic acid. Due to this composition, cardiolipin exhibits a conical structure, which allows for membrane curvature called cristae. Such qualities allow CL to play essential roles in maintaining mitochondrial shape, energy production, and protein transport within cells.[5] During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved.

Influence of cardiolipin on the respiratory chain

Cardiolipin has been shown to assist in energy production of the mitochondria. Several proteins in the mitochondrial respiratory chain require CL for optimal function.[13] CL has been found to be involved in the stabilization of each respiratory chain complex, enabling efficient electron transport.[14] CL assists in forming super-complexes with proteins localized in the inner mitochondrial matrix, which include the ATP/ADP translocase, pyruvate carrier, carnitine carrier, and all of the respiratory chain complexes (I, III,IV, V).[15][16] CL also enables trapping of protons in the intermembrane space, aiding ATP synthase to carry out its function of channeling protons into the mitochondrial matrix.[12]


Clinical significance

Mutations in the TAZ gene have been associated with a number of mitochondrial deficiencies and associated disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC).[1] TAZ has also been associated with various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.[6][7][8]

Barth Syndrome

Barth syndrome is an X-linked disease caused by mutations in the TAZ gene.[17][18] More than 160 mutations in the TAZ gene have been found to this disease. It is a rare condition that occurs almost exclusively in males. TAZ gene mutations that cause barth syndrome result in the production of tafazzin proteins with little or no function. As a result, linoleic acid is not added to cardiolipin, which causes problems with normal mitochondrial shape and functions such as energy production and protein transport. Tissues with high energy demands, such as the heart and other muscles, are most susceptible to cell death due to reduced energy production in mitochondria. Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections. Dysfunctional mitochondria likely lead to other signs and symptoms of Barth syndrome.[5]

Common clinical manifestations include:[5][17][18]

Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.[17][18]

A c.348C>T mutation resulted in dilated cardiomyopathy with noncompaction of the ventricular myocardium.[19] A frame shift mutation of c.227delC displayed symptoms of neutropenia, cardiomegaly, and other common symptoms of Bath Syndrome.[20] Another a c.C153G mutation resulted in severe metabolic acidosis, cardiomegaly, and other major symptoms of Barth syndrome.[21]

In conclusion, tafazzin is responsible for remodeling of a phospholipid cardiolipin (CL),[22] the signature lipid of the mitochondrial inner membrane. Therefore, a dysfunctioning tafazzin has been found to lead to an impaired mitochondrial respiratory chain. As a result, Barth syndrome patients exhibit defects in cardiolipin metabolism, including aberrant cardiolipin fatty acyl composition, accumulation of monolysocardiolipin (MLCL) and reduced total cardiolipin levels.[23][24] This may lead to acute metabolic decompensation and sudden death. Cardiac transplantation is the only possibility at the present time.[21]

Dilated cardiomyopathy (DCM)

Some mutations in the TAZ gene cause dilated cardiomyopathy without the other features of Barth syndrome. Dilated cardiomyopathy is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently, often resulting in heart failure. The decreased blood flow can lead to swelling in the legs and abdomen, fluid in the lungs, and an increased risk of blood clots.[5]

Isolated noncompaction of left ventricular myocardium (INVM)

Mutations in the TAZ gene can cause a heart condition called isolated noncompaction of left ventricular myocardium (INVM). This condition occurs when the lower left chamber of the heart (left ventricle) does not develop correctly. In INVM, the heart muscle is weakened and cannot pump blood efficiently. Abnormal heart rhythms (arrhythmias) can also occur. INVM frequently causes heart failure.[5]

Cancer

Highly elevated TAZ activity has been linked to tumorigenesis and oncogenic activity. It has also been associated with and various cancers, including breast cancer, papillary thyroid carcinoma and non-small cell lung cancer, and glioma.[6] In breast cancer, TAZ has been shown to be required for cancer cells to sustain self-renewal and create tumors.[25] Additionally, TAZ has been found to be highly expressed in gastric cancer cells resistant to cisplatin. This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT). The findings that TAZ is involved in inducing EMT as well as its high levels in these cancer cells may point to its involvement in gastric cancer.[6][7] High expression of TAZ was also found in rectal cancer and thyroid neoplasms, indicating that TAZ may promote tumorigenesis and inhibit apoptosis.[8] In a study of 140 Swedish rectal cancer patients, high levels of TAZ was linked to rectal cancer development. Additionally, the levels of TAZ were connected to the radiotherapy response of the patients, potentially offering insight into cancer recurrence in patients.[26] A potential link between PI3K and TAZ indicates a possible association between PI3K signaling and TAZ as both were highly elevated in PTEN mutant cancer cells.[6]

Interactions

TAZ has been shown to have protein-protein interactions with the following and more.[27][17]


History

The protein was identified by Italian scientists Silvia Bione et al. in 1996.[11] Owing to the complex procedure required for the identification of tafazzin, the protein was named after "Tafazzi", a masochistic comic character in an Italian television show.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Entrez Gene: tafazzin". This article incorporates text from this source, which is in the public domain.
  2. ↑ Xu Y, Zhang S, Malhotra A, Edelman-Novemsky I, Ma J, Kruppa A, Cernicica C, Blais S, Neubert TA, Ren M, Schlame M (October 2009). "Characterization of tafazzin splice variants from humans and fruit flies". The Journal of Biological Chemistry. 284 (42): 29230–9. doi:10.1074/jbc.M109.016642. PMC 2781466. PMID 19700766.
  3. ↑ Xu Y, Malhotra A, Ren M, Schlame M (December 2006). "The enzymatic function of tafazzin". The Journal of Biological Chemistry. 281 (51): 39217–24. doi:10.1074/jbc.M606100200. PMID 17082194.
  4. ↑ 4.0 4.1 Acehan D, Vaz F, Houtkooper RH, James J, Moore V, Tokunaga C, Kulik W, Wansapura J, Toth MJ, Strauss A, Khuchua Z (January 2011). "Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome". The Journal of Biological Chemistry. 286 (2): 899–908. doi:10.1074/jbc.M110.171439. PMC 3020775. PMID 21068380.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 "TAZ". Genetics Home Reference. NCBI. This article incorporates text from this source, which is in the public domain.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Huang W, Lv X, Liu C, Zha Z, Zhang H, Jiang Y, Xiong Y, Lei QY, Guan KL (July 2012). "The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition". The Journal of Biological Chemistry. 287 (31): 26245–53. doi:10.1074/jbc.M112.382036. PMC 3406709. PMID 22692215.
  7. ↑ 7.0 7.1 7.2 Ge L, Li DS, Chen F, Feng JD, Li B, Wang TJ (July 2017). "TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells". International Journal of Oncology. 51 (1): 307–315. doi:10.3892/ijo.2017.3998. PMID 28534974.
  8. ↑ 8.0 8.1 8.2 Chen M, Zhang Y, Zheng PS (2017). "Tafazzin (TAZ) promotes the tumorigenicity of cervical cancer cells and inhibits apoptosis". PLOS One. 12 (5): e0177171. doi:10.1371/journal.pone.0177171. PMC 5425199. PMID 28489874.
  9. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  10. ↑ "TAZ Tafazzin". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  11. ↑ 11.0 11.1 Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D (April 1996). "A novel X-linked gene, G4.5. is responsible for Barth syndrome". Nature Genetics. 12 (4): 385–9. doi:10.1038/ng0496-385. PMID 8630491.
  12. ↑ 12.0 12.1 Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Pérez-Cerdá C, Morrone A, Malvagia S, Wanders RJ, Kulik W, Vaz FM (October 2009). "The enigmatic role of tafazzin in cardiolipin metabolism". Biochimica et Biophysica Acta. 1788 (10): 2003–14. doi:10.1016/j.bbamem.2009.07.009. PMID 19619503.
  13. ↑ Houtkooper RH, Vaz FM (August 2008). "Cardiolipin, the heart of mitochondrial metabolism". Cellular and Molecular Life Sciences. 65 (16): 2493–506. doi:10.1007/s00018-008-8030-5. PMID 18425414.
  14. ↑ Brandner K, Mick DU, Frazier AE, Taylor RD, Meisinger C, Rehling P (November 2005). "Taz1, an outer mitochondrial membrane protein, affects stability and assembly of inner membrane protein complexes: implications for Barth Syndrome". Molecular Biology of the Cell. 16 (11): 5202–14. doi:10.1091/mbc.e05-03-0256. PMC 1266419. PMID 16135531.
  15. ↑ Barth, PG; Valianpour, F; Bowen, VM; Lam, J; Duran, M; Vaz, FM; Wanders, RJ (1 May 2004). "X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update". American Journal of Medical Genetics Part A. 126A (4): 349–54. doi:10.1002/ajmg.a.20660. PMID 15098233.
  16. ↑ Hoffmann B, Stöckl A, Schlame M, Beyer K, Klingenberg M (January 1994). "The reconstituted ADP/ATP carrier activity has an absolute requirement for cardiolipin as shown in cysteine mutants". The Journal of Biological Chemistry. 269 (3): 1940–4. PMID 8294444.
  17. ↑ 17.0 17.1 17.2 17.3 "TAZ - Tafazzin - Homo sapiens (Human) - TAZ gene & protein". Retrieved 2018-08-24.
  18. ↑ 18.0 18.1 18.2 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  19. ↑ Ferri L, Dionisi-Vici C, Taurisano R, Vaz FM, Guerrini R, Morrone A (November 2016). "When silence is noise: infantile-onset Barth syndrome caused by a synonymous substitution affecting TAZ gene transcription". Clinical Genetics. 90 (5): 461–465. doi:10.1111/cge.12756. PMID 26853223.
  20. ↑ Kim GB, Kwon BS, Bae EJ, Noh CI, Seong MW, Park SS (May 2013). "A novel mutation of the TAZ gene in Barth syndrome: acute exacerbation after contrast-dye injection". Journal of Korean Medical Science. 28 (5): 784–7. doi:10.3346/jkms.2013.28.5.784. PMC 3653095. PMID 23678274.
  21. ↑ 21.0 21.1 Yen TY, Hwu WL, Chien YH, Wu MH, Lin MT, Tsao LY, Hsieh WS, Lee NC (August 2008). "Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review". European Journal of Pediatrics. 167 (8): 941–4. doi:10.1007/s00431-007-0592-y. PMID 17846786.
  22. ↑ Neuwald AF (August 1997). "Barth syndrome may be due to an acyltransferase deficiency". Current Biology. 7 (8): R465–6. doi:10.1016/S0960-9822(06)00237-5. PMID 9259571.
  23. ↑ Barth PG, Wanders RJ, Vreken P, Janssen EA, Lam J, Baas F (June 1999). "X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060)". Journal of Inherited Metabolic Disease. 22 (4): 555–67. doi:10.1023/A:1005568609936. PMID 10407787.
  24. ↑ Valianpour F, Mitsakos V, Schlemmer D, Towbin JA, Taylor JM, Ekert PG, Thorburn DR, Munnich A, Wanders RJ, Barth PG, Vaz FM (June 2005). "Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis". Journal of Lipid Research. 46 (6): 1182–95. doi:10.1194/jlr.M500056-JLR200. PMID 15805542.
  25. ↑ Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, Inui M, Montagner M, Parenti AR, Poletti A, Daidone MG, Dupont S, Basso G, Bicciato S, Piccolo S (November 2011). "The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells". Cell. 147 (4): 759–72. doi:10.1016/j.cell.2011.09.048. PMID 22078877.
  26. ↑ Pathak S, Meng WJ, Zhang H, Gnosa S, Nandy SK, Adell G, Holmlund B, Sun XF (2014). "Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy". PLOS One. 9 (5): e98317. doi:10.1371/journal.pone.0098317. PMC 4032294. PMID 24858921.
  27. ↑ Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P (December 2012). "MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation". Cell. 151 (7): 1528–41. doi:10.1016/j.cell.2012.11.053. PMID 23260140.

Further reading

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