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{{Infobox_gene}}
{{Infobox_gene}}


'''NADH:ubiquinone oxidoreductase complex assembly factor 4''' is a [[protein]] that in humans is encoded by the NDUFAF4 [[gene]].
'''NADH:ubiquinone oxidoreductase complex assembly factor 4,''' (NDUFAF4) also known as '''Hormone-regulated proliferation-associated protein of 20 kDa,''' (HRPAP20) or '''C6orf66''' is a [[protein]] that in humans is encoded by the ''NDUFAF4'' [[gene]].<ref name="entrez">
<ref name="entrez">
{{cite web
{{cite web
| title = Entrez Gene: NADH:ubiquinone oxidoreductase complex assembly factor 4
| title = Entrez Gene: NADH:ubiquinone oxidoreductase complex assembly factor 4
| url = https://www.ncbi.nlm.nih.gov/gene/29078
| url = https://www.ncbi.nlm.nih.gov/gene/29078
| accessdate = 2017-08-07
| access-date = 2017-08-07
}}</ref>
}}</ref><ref name=":0" /> NDUFAF4 is a [[Mitochondrion|mitochondrial]] assembly protein involved in the assembly of [[NADH dehydrogenase (ubiquinone)]] also known as [[complex I]], which is located in the [[mitochondrial inner membrane]] and is the largest of the five complexes of the [[electron transport chain]].<ref name="Biochem">{{cite book|title=Fundamentals of biochemistry : life at the molecular level|author=Donald Voet|author2=Judith G. Voet|author3=Charlotte W. Pratt|date=2013|publisher=Wiley|isbn=9780470547847|edition=4th|location=Hoboken, NJ|pages=581–620|chapter=18}}</ref><ref name=":3" /> [[Mutation|Mutations]] in this gene have been associated with complex I deficiency and infantile mitochondrial [[Encephalopathy|encephalomyopathy]].<ref name="entrez" /><ref name=":0" /><ref name=":3" /> Elevations in HRPAP20 have also been implicated in [[breast cancer]].<ref name=":6" />


==Function==
== Structure ==
<i>NDUFAF4</i> is located on the [[Locus (genetics)|q arm]] of [[chromosome]] 6 in position 16.1 and has 3 [[Exon|exons]].<ref name="entrez" /> The <i>NDUFAF4</i> gene produces a 23.7 kDa protein composed of 203 [[Amino acid|amino acids]].<ref>{{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>{{Cite web|url=https://amino.heartproteome.org/web/protein/Q9VH39|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-07-26}}</ref> HRPAP20 is a [[phosphoprotein]], containing a [[Phosphate|phosphate group]] attachment and, potentially, multiple [[kinase]] recognition sequences. Additionally, it has a CaM-binding sequence that allows it to interact with [[calmodulin]] (CaM), which itself is involved in numerous cellular processes.<ref name=":6" />


NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from [[NADH]] to [[ubiquinone]] (coenzyme Q) in the first step of the [[mitochondrial respiratory chain]], resulting in the translocation of protons across the [[inner mitochondrial membrane]]. This gene encodes a [[complex I]] assembly factor. Mutations in this gene are a cause of [[mitochondrial complex I deficiency]].
== Function ==
 
NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from [[NADH]] to [[ubiquinone]] (coenzyme Q) in the first step of the [[mitochondrial respiratory chain]], resulting in the translocation of protons across the [[inner mitochondrial membrane]]. <i>NDUFAF4</i> encodes a [[complex I]] assembly factor that is important for the correct assembly and function of complex I.<ref name="entrez" /> NDUFAF4 [[Colocalization|colocalizes]], comigrates to several assembly intermediates, and is codependent with [[NDUFAF3]] from the early to late stages of complex I assembly. In addition to their close interactions with each other, NDUFAF4 and NDUFAF3 interact with [[NDUFS2]], [[NDUFS3]], [[NDUFS8]], and [[NDUFA5]] in a [[Translation (biology)|translation]]-dependent early assembly mechanism.<ref name=":5">{{cite journal | vauthors = Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG | title = Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease | journal = American Journal of Human Genetics | volume = 84 | issue = 6 | pages = 718–27 | date = June 2009 | pmid = 19463981 | pmc = 2694978 | doi = 10.1016/j.ajhg.2009.04.020 }}</ref> NDUFAF4 has also been shown to play a role in growth and [[apoptosis]] regulation through a CaM-mediated mechanism involving [[MMP9|MMP-9]] secretion.<ref name=":6" /></p>
 
== Clinical Significance ==
Mutations in ''NDUFAF4 (HRPAP20)'' have been associated with mitochondrial complex I deficiency,<ref name="entrez" /> infantile mitochondrial [[Encephalopathy|encephalomyopathy]].<ref name=":3">{{cite journal | vauthors = Saada A, Edvardson S, Rapoport M, Shaag A, Amry K, Miller C, Lorberboum-Galski H, Elpeleg O | title = C6ORF66 is an assembly factor of mitochondrial complex I | journal = American Journal of Human Genetics | volume = 82 | issue = 1 | pages = 32–8 | date = January 2008 | pmid = 18179882 | pmc = 2253982 | doi = 10.1016/j.ajhg.2007.08.003 }}</ref> Additionally, research analyzing HRPAP20's effect on human cancer cells have suggested that it plays a role in [[Metastasis|tumor metastasis]], malignant progression, and [[breast cancer]].<ref name=":6">{{cite journal | vauthors = Karp CM, Shukla MN, Buckley DJ, Buckley AR | title = HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion | journal = Oncogene | volume = 26 | issue = 12 | pages = 1780–8 | date = March 2007 | pmid = 17001319 | doi = 10.1038/sj.onc.1209980 }}</ref>
 
Mitochondrial diseases are disorders that are the result of the dysfunction of the mitochondrial respiratory chain. They can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset [[Neurodegeneration|neurodegenerative disorders]]. Phenotypes include [[macrocephaly]] with progressive [[leukodystrophy]], non-specific [[encephalopathy]], [[cardiomyopathy]], [[myopathy]], [[liver disease]], [[Leigh syndrome]], [[Leber's hereditary optic neuropathy|Leber hereditary optic neuropathy]], and some forms of [[Parkinson's disease|Parkinson disease]].<ref name=":0">{{Cite web| url=https://www.uniprot.org/uniprot/Q9P032 |title=NDUFAF4 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4 - Homo sapiens (Human) - NDUFAF4 gene & protein|website=www.uniprot.org |access-date=2018-07-26}}</ref><ref name=":4">{{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> Pathogenic mutations have been linked to changes in a 2.6 Mb critical region (97.17–99.77 Mb) on chromosome 6 and have included a T→C substitution at p. 194 in exon 2 that predicts a Leu65Pro variant. Clinically, ''NDUFAF4'' mutations have been associated with infantile mitochondrial encephalomyopathy, with [[lactic acidosis]], [[nystagmus]], [[hypotonia]], [[cardiomyopathy]], [[cerebral atrophy]], and generalized tonic-clonic convulsions as some possible symptoms.<ref name=":3" />
 
''HRPAP20'' was found to be significantly elevated in patient breast tumors as compared to normal tissue. Further analysis using tumor cell lines with constitutively expressed HRPAP20 suggests that it increases the invasiveness, proliferation, and apoptotic suppression of breast cancer cells. This is often indicative of tumor metastasis and malignant progression.<ref name=":6" />
 
== Interactions ==
NDUFAF4 (HRPAP20) has been shown to interact closely with [[NDUFAF3]] as well as with [[NDUFS2]], [[NDUFS3]], [[NDUFS8]], and [[NDUFA5]] in the mitochondrial inner membrane.<ref name=":5" /> HRPAP20 also interacts with [[calmodulin]] (CaM) in a mechanism that results in increased [[MMP9|MMP-9]] secretion, associated with increased invasiveness in breast cancer cells.<ref name=":6" /> In addition to co-complexes, NDUFAF4 has protein-protein interactions with [[WDR26]].<ref>{{Cite web|url=https://www.ebi.ac.uk/intact/interaction/EBI-11931712?conversationContext=1&kmr=true|title=ndufaf4-wdr26-1 | work = IntAct |access-date=2018-07-26}}</ref>


== References ==
== References ==
{{reflist}}
{{reflist}}


== Further reading ==
== Further reading ==
 
{{refbegin}}
{{refbegin |30em}}
* {{cite journal | vauthors = Karp CM, Shukla MN, Buckley DJ, Buckley AR | title = HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion | journal = Oncogene | volume = 26 | issue = 12 | pages = 1780–8 | date = March 2007 | pmid = 17001319 | doi = 10.1038/sj.onc.1209980 }}
*{{cite journal |vauthors=Karp CM, Shukla MN, Buckley DJ, Buckley AR |title=HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion |journal=Oncogene |volume=26 |issue=12 |pages=1780–8 |year=2007 |pmid=17001319 |doi=10.1038/sj.onc.1209980 |url=}}
* {{cite journal | vauthors = Tozlu-Kara S, Roux V, Andrieu C, Vendrell J, Vacher S, Lazar V, Spyratos F, Tubiana-Hulin M, Cohen P, Dessen P, Lidereau R, Bièche I | title = Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen | journal = Journal of Molecular Endocrinology | volume = 39 | issue = 4 | pages = 305–18 | date = October 2007 | pmid = 17909269 | doi = 10.1677/JME-07-0001 }}
*{{cite journal |vauthors=Tozlu-Kara S, Roux V, Andrieu C, Vendrell J, Vacher S, Lazar V, Spyratos F, Tubiana-Hulin M, Cohen P, Dessen P, Lidereau R, Bièche I |title=Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen |journal=J. Mol. Endocrinol. |volume=39 |issue=4 |pages=305–18 |year=2007 |pmid=17909269 |doi=10.1677/JME-07-0001 |url=}}
* {{cite journal | vauthors = Zimmermann FA, Mayr JA, Neureiter D, Feichtinger R, Alinger B, Jones ND, Eder W, Sperl W, Kofler B | title = Lack of complex I is associated with oncocytic thyroid tumours | journal = British Journal of Cancer | volume = 100 | issue = 9 | pages = 1434–7 | date = May 2009 | pmid = 19352385 | pmc = 2694433 | doi = 10.1038/sj.bjc.6605028 }}
*{{cite journal |vauthors=Saada A, Edvardson S, Rapoport M, Shaag A, Amry K, Miller C, Lorberboum-Galski H, Elpeleg O |title=C6ORF66 is an assembly factor of mitochondrial complex I |journal=Am. J. Hum. Genet. |volume=82 |issue=1 |pages=32–8 |year=2008 |pmid=18179882 |pmc=2253982 |doi=10.1016/j.ajhg.2007.08.003 |url=}}
*{{cite journal |vauthors=Zimmermann FA, Mayr JA, Neureiter D, Feichtinger R, Alinger B, Jones ND, Eder W, Sperl W, Kofler B |title=Lack of complex I is associated with oncocytic thyroid tumours |journal=Br. J. Cancer |volume=100 |issue=9 |pages=1434–7 |year=2009 |pmid=19352385 |pmc=2694433 |doi=10.1038/sj.bjc.6605028 |url=}}
*{{cite journal |vauthors=Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG |title=Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease |journal=Am. J. Hum. Genet. |volume=84 |issue=6 |pages=718–27 |year=2009 |pmid=19463981 |pmc=2694978 |doi=10.1016/j.ajhg.2009.04.020 |url=}}
 
{{refend}}
{{refend}}


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Latest revision as of 15:10, 11 September 2018

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Orthologs
SpeciesHumanMouse
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NADH:ubiquinone oxidoreductase complex assembly factor 4, (NDUFAF4) also known as Hormone-regulated proliferation-associated protein of 20 kDa, (HRPAP20) or C6orf66 is a protein that in humans is encoded by the NDUFAF4 gene.[1][2] NDUFAF4 is a mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[3][4] Mutations in this gene have been associated with complex I deficiency and infantile mitochondrial encephalomyopathy.[1][2][4] Elevations in HRPAP20 have also been implicated in breast cancer.[5]

Structure

NDUFAF4 is located on the q arm of chromosome 6 in position 16.1 and has 3 exons.[1] The NDUFAF4 gene produces a 23.7 kDa protein composed of 203 amino acids.[6][7] HRPAP20 is a phosphoprotein, containing a phosphate group attachment and, potentially, multiple kinase recognition sequences. Additionally, it has a CaM-binding sequence that allows it to interact with calmodulin (CaM), which itself is involved in numerous cellular processes.[5]

Function

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. NDUFAF4 encodes a complex I assembly factor that is important for the correct assembly and function of complex I.[1] NDUFAF4 colocalizes, comigrates to several assembly intermediates, and is codependent with NDUFAF3 from the early to late stages of complex I assembly. In addition to their close interactions with each other, NDUFAF4 and NDUFAF3 interact with NDUFS2, NDUFS3, NDUFS8, and NDUFA5 in a translation-dependent early assembly mechanism.[8] NDUFAF4 has also been shown to play a role in growth and apoptosis regulation through a CaM-mediated mechanism involving MMP-9 secretion.[5]

Clinical Significance

Mutations in NDUFAF4 (HRPAP20) have been associated with mitochondrial complex I deficiency,[1] infantile mitochondrial encephalomyopathy.[4] Additionally, research analyzing HRPAP20's effect on human cancer cells have suggested that it plays a role in tumor metastasis, malignant progression, and breast cancer.[5]

Mitochondrial diseases are disorders that are the result of the dysfunction of the mitochondrial respiratory chain. They can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[2][9] Pathogenic mutations have been linked to changes in a 2.6 Mb critical region (97.17–99.77 Mb) on chromosome 6 and have included a T→C substitution at p. 194 in exon 2 that predicts a Leu65Pro variant. Clinically, NDUFAF4 mutations have been associated with infantile mitochondrial encephalomyopathy, with lactic acidosis, nystagmus, hypotonia, cardiomyopathy, cerebral atrophy, and generalized tonic-clonic convulsions as some possible symptoms.[4]

HRPAP20 was found to be significantly elevated in patient breast tumors as compared to normal tissue. Further analysis using tumor cell lines with constitutively expressed HRPAP20 suggests that it increases the invasiveness, proliferation, and apoptotic suppression of breast cancer cells. This is often indicative of tumor metastasis and malignant progression.[5]

Interactions

NDUFAF4 (HRPAP20) has been shown to interact closely with NDUFAF3 as well as with NDUFS2, NDUFS3, NDUFS8, and NDUFA5 in the mitochondrial inner membrane.[8] HRPAP20 also interacts with calmodulin (CaM) in a mechanism that results in increased MMP-9 secretion, associated with increased invasiveness in breast cancer cells.[5] In addition to co-complexes, NDUFAF4 has protein-protein interactions with WDR26.[10]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Entrez Gene: NADH:ubiquinone oxidoreductase complex assembly factor 4". Retrieved 2017-08-07.
  2. ↑ 2.0 2.1 2.2 "NDUFAF4 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 4 - Homo sapiens (Human) - NDUFAF4 gene & protein". www.uniprot.org. Retrieved 2018-07-26.
  3. ↑ Donald Voet; Judith G. Voet; Charlotte W. Pratt (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 9780470547847.
  4. ↑ 4.0 4.1 4.2 4.3 Saada A, Edvardson S, Rapoport M, Shaag A, Amry K, Miller C, Lorberboum-Galski H, Elpeleg O (January 2008). "C6ORF66 is an assembly factor of mitochondrial complex I". American Journal of Human Genetics. 82 (1): 32–8. doi:10.1016/j.ajhg.2007.08.003. PMC 2253982. PMID 18179882.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Karp CM, Shukla MN, Buckley DJ, Buckley AR (March 2007). "HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion". Oncogene. 26 (12): 1780–8. doi:10.1038/sj.onc.1209980. PMID 17001319.
  6. ↑ 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.
  7. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-07-26.
  8. ↑ 8.0 8.1 Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG (June 2009). "Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease". American Journal of Human Genetics. 84 (6): 718–27. doi:10.1016/j.ajhg.2009.04.020. PMC 2694978. PMID 19463981.
  9. ↑ "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  10. ↑ "ndufaf4-wdr26-1". IntAct. Retrieved 2018-07-26.

Further reading

  • Karp CM, Shukla MN, Buckley DJ, Buckley AR (March 2007). "HRPAP20: a novel calmodulin-binding protein that increases breast cancer cell invasion". Oncogene. 26 (12): 1780–8. doi:10.1038/sj.onc.1209980. PMID 17001319.
  • Tozlu-Kara S, Roux V, Andrieu C, Vendrell J, Vacher S, Lazar V, Spyratos F, Tubiana-Hulin M, Cohen P, Dessen P, Lidereau R, Bièche I (October 2007). "Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen". Journal of Molecular Endocrinology. 39 (4): 305–18. doi:10.1677/JME-07-0001. PMID 17909269.
  • Zimmermann FA, Mayr JA, Neureiter D, Feichtinger R, Alinger B, Jones ND, Eder W, Sperl W, Kofler B (May 2009). "Lack of complex I is associated with oncocytic thyroid tumours". British Journal of Cancer. 100 (9): 1434–7. doi:10.1038/sj.bjc.6605028. PMC 2694433. PMID 19352385.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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