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{{Infobox_gene}}
{{Infobox_gene}}
'''Pitrilysin metallopeptidase 1''' also known as '''presequence protease, mitochondrial''' (PreP) and '''metalloprotease 1''' (MTP-1) is an [[enzyme]] that in humans is encoded by the ''PITRM1'' [[gene]].<ref name="pmid1036083">{{cite journal | vauthors = Marusov EV | title = [Ecological sterotypes of defensive behavior in fish under the action of chemical danger signals] | journal = Nauchnye Doklady Vyssheĭ Shkoly. Biologicheskie Nauki | volume =  | issue = 8 | pages = 67–9 | date = Jul 1977 | pmid = 1036083 | pmc =  | doi =  }}</ref><ref name="pmid10470851">{{cite journal | vauthors = Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 6 | issue = 3 | pages = 197–205 | date = June 1999 | pmid = 10470851 | pmc =  | doi = 10.1093/dnares/6.3.197 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PITRM1 pitrilysin metallopeptidase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10531| accessdate = }}</ref> It is also sometimes called metalloprotease 1 (MP1).PreP facilitates [[proteostasis]] by utilizing an ~13300-A(3) catalytic chamber to degrade toxic peptides, including mitochondrial presequences and [[β-amyloid]].<ref name="pmid24931469">{{cite journal | vauthors = King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ | title = Molecular basis of substrate recognition and degradation by human presequence protease | journal = Structure | volume = 22 | issue = 7 | pages = 996–1007 | date = July 2014 | pmid = 24931469 | doi = 10.1016/j.str.2014.05.003 | pmc=4128088}}</ref> Deficiency of PreP is found associated with [[Alzheimer’s disease]].
'''Pitrilysin metallopeptidase 1''' also known as '''presequence protease, mitochondrial''' (PreP) and '''metalloprotease 1''' (MTP-1) is an [[enzyme]] that in humans is encoded by the ''PITRM1'' [[gene]].<ref name="pmid1036083">{{cite journal | vauthors = Marusov EV | title = [Ecological sterotypes of defensive behavior in fish under the action of chemical danger signals] | journal = Nauchnye Doklady Vysshei Shkoly. Biologicheskie Nauki | volume =  | issue = 8 | pages = 67–9 | date = July 1977 | pmid = 1036083 | pmc =  | doi =  }}</ref><ref name="pmid10470851">{{cite journal | vauthors = Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 6 | issue = 3 | pages = 197–205 | date = June 1999 | pmid = 10470851 | pmc =  | doi = 10.1093/dnares/6.3.197 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PITRM1 pitrilysin metallopeptidase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10531| access-date = }}</ref> It is also sometimes called metalloprotease 1 (MP1).PreP facilitates [[proteostasis]] by utilizing an ~13300-A(3) catalytic chamber to degrade toxic peptides, including mitochondrial presequences and [[β-amyloid]].<ref name="pmid24931469">{{cite journal | vauthors = King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ | title = Molecular basis of substrate recognition and degradation by human presequence protease | journal = Structure | volume = 22 | issue = 7 | pages = 996–1007 | date = July 2014 | pmid = 24931469 | pmc = 4128088 | doi = 10.1016/j.str.2014.05.003 }}</ref> Deficiency of PreP is found associated with [[Alzheimer’s disease]]. Reduced levels of PreP via RNAi mediated knockdown have been shown to lead to defective maturation of the protein Frataxin.<ref name="ReferenceA">{{cite journal | vauthors = Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE | title = Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 18251 | date = December 2015 | pmid = 26671574 | pmc = 4680912 | doi = 10.1038/srep18251 }}</ref>


==Structure==
== Structure ==


===Gene===
===Gene===
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== Function ==
== Function ==


PreP is an Zn<sup>2+</sup>-dependent and [[Adenosine triphosphate|ATP]]-independent [[metalloprotease]], it doesn’t select substrates on the basis of post-translational modifications or embedded degradation tags.<ref name="pmid18470479">{{cite journal | vauthors = Malito E, Hulse RE, Tang WJ | title = Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 16 | pages = 2574–85 | date = August 2008 | pmid = 18470479 | doi = 10.1007/s00018-008-8112-4 | pmc=2756532}}</ref><ref name="pmid18698327">{{cite journal | vauthors = Ravid T, Hochstrasser M | title = Diversity of degradation signals in the ubiquitin-proteasome system | journal = Nature Reviews Molecular Cell Biology | volume = 9 | issue = 9 | pages = 679–90 | date = September 2008 | pmid = 18698327 | doi = 10.1038/nrm2468 | pmc=2606094}}</ref><ref name="pmid21469952">{{cite journal | vauthors = Sauer RT, Baker TA | title = AAA+ proteases: ATP-fueled machines of protein destruction | journal = Annual Review of Biochemistry | volume = 80 | pages = 587–612 | date = 2011 | pmid = 21469952 | doi = 10.1146/annurev-biochem-060408-172623 }}</ref> Instead, it uses a negatively charged catalytic chamber to engulf substrates peptides of up to ~65 residues while excluding larger, folded proteins.<ref name="pmid16849325">{{cite journal | vauthors = Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E | title = Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP | journal = The Journal of Biological Chemistry | volume = 281 | issue = 39 | pages = 29096–104 | date = September 2006 | pmid = 16849325 | doi = 10.1074/jbc.M602532200 }}</ref><ref name="pmid16601675">{{cite journal | vauthors = Johnson KA, Bhushan S, Ståhl A, Hallberg BM, Frohn A, Glaser E, Eneqvist T | title = The closed structure of presequence protease PreP forms a unique 10,000 Angstroms3 chamber for proteolysis | journal = The EMBO Journal | volume = 25 | issue = 9 | pages = 1977–86 | date = May 2006 | pmid = 16601675 | doi = 10.1038/sj.emboj.7601080 | pmc=1456932}}</ref> It primarily localizes to the mitochondrial matrix, and cuts a range of peptides into recyclable fragments.<ref name="pmid21621546">{{cite journal | vauthors = Alikhani N, Berglund AK, Engmann T, Spånning E, Vögtle FN, Pavlov P, Meisinger C, Langer T, Glaser E | title = Targeting capacity and conservation of PreP homologues localization in mitochondria of different species | journal = Journal of Molecular Biology | volume = 410 | issue = 3 | pages = 400–10 | date = July 2011 | pmid = 21621546 | doi = 10.1016/j.jmb.2011.05.009 }}</ref><ref name="pmid19196155">{{cite journal | vauthors = Chow KM, Gakh O, Payne IC, Juliano MA, Juliano L, Isaya G, Hersh LB | title = Mammalian pitrilysin: substrate specificity and mitochondrial targeting | journal = Biochemistry | volume = 48 | issue = 13 | pages = 2868–77 | date = April 2009 | pmid = 19196155 | doi = 10.1021/bi8016125 | pmc=2765508}}</ref> The substrates of PreP are vital to proteostasis, as they can insert to mitochondrial membranes, disrupting [[electrical potential]] and uncoupling respiration.<ref name="pmid17562452">{{cite journal | vauthors = Koppen M, Langer T | title = Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 42 | issue = 3 | pages = 221–42 | date = 2007 | pmid = 17562452 | doi = 10.1080/10409230701380452 }}</ref><ref name="pmid22172993">{{cite journal | vauthors = Mossmann D, Meisinger C, Vögtle FN | title = Processing of mitochondrial presequences | journal = Biochimica et Biophysica Acta | volume = 1819 | issue = 9-10 | pages = 1098–106 | date = 2012 | pmid = 22172993 | doi = 10.1016/j.bbagrm.2011.11.007 }}</ref> Thus deletion of ''PRTRM1'' leads to a delayed growth phenotype.<ref name="pmid15772085">{{cite journal | vauthors = Kambacheld M, Augustin S, Tatsuta T, Müller S, Langer T | title = Role of the novel metallopeptidase Mop112 and saccharolysin for the complete degradation of proteins residing in different subcompartments of mitochondria | journal = The Journal of Biological Chemistry | volume = 280 | issue = 20 | pages = 20132–9 | date = May 2005 | pmid = 15772085 | doi = 10.1074/jbc.M500398200 }}</ref><ref name="pmid19701724">{{cite journal | vauthors = Nilsson Cederholm S, Bäckman HG, Pesaresi P, Leister D, Glaser E | title = Deletion of an organellar peptidasome PreP affects early development in Arabidopsis thaliana | journal = Plant Molecular Biology | volume = 71 | issue = 4-5 | pages = 497–508 | date = November 2009 | pmid = 19701724 | doi = 10.1007/s11103-009-9534-6 }}</ref> Notabley, PreP degrades several functionally relevant Aβ species, the aggregates of which are toxic to the [[neuron]] and play a key role in AD pathogenesis.<ref name="pmid21750375">{{cite journal | vauthors = Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS | title = Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria | journal = Journal of Alzheimer's Disease | volume = 27 | issue = 1 | pages = 75–87 | date = 2011 | pmid = 21750375 | doi = 10.3233/JAD-2011-101716 | pmc=3381900}}</ref><ref name="pmid16849325"/><ref name="pmid19962426">{{cite journal | vauthors = Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C | title = Genetic and biochemical studies of SNPs of the mitochondrial A beta-degrading protease, hPreP | journal = Neuroscience Letters | volume = 469 | issue = 2 | pages = 204–8 | date = January 2010 | pmid = 19962426 | doi = 10.1016/j.neulet.2009.11.075 }}</ref>
PreP is an Zn<sup>2+</sup>-dependent and [[Adenosine triphosphate|ATP]]-independent [[metalloprotease]], it doesn’t select substrates on the basis of post-translational modifications or embedded degradation tags.<ref name="pmid18470479">{{cite journal | vauthors = Malito E, Hulse RE, Tang WJ | title = Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 16 | pages = 2574–85 | date = August 2008 | pmid = 18470479 | pmc = 2756532 | doi = 10.1007/s00018-008-8112-4 }}</ref><ref name="pmid18698327">{{cite journal | vauthors = Ravid T, Hochstrasser M | title = Diversity of degradation signals in the ubiquitin-proteasome system | journal = Nature Reviews. Molecular Cell Biology | volume = 9 | issue = 9 | pages = 679–90 | date = September 2008 | pmid = 18698327 | pmc = 2606094 | doi = 10.1038/nrm2468 }}</ref><ref name="pmid21469952">{{cite journal | vauthors = Sauer RT, Baker TA | title = AAA+ proteases: ATP-fueled machines of protein destruction | journal = Annual Review of Biochemistry | volume = 80 | pages = 587–612 | date = 2011 | pmid = 21469952 | doi = 10.1146/annurev-biochem-060408-172623 }}</ref> Instead, it uses a negatively charged catalytic chamber to engulf substrates peptides of up to ~65 residues while excluding larger, folded proteins.<ref name="pmid16849325">{{cite journal | vauthors = Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E | title = Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP | journal = The Journal of Biological Chemistry | volume = 281 | issue = 39 | pages = 29096–104 | date = September 2006 | pmid = 16849325 | doi = 10.1074/jbc.M602532200 }}</ref><ref name="pmid16601675">{{cite journal | vauthors = Johnson KA, Bhushan S, Ståhl A, Hallberg BM, Frohn A, Glaser E, Eneqvist T | title = The closed structure of presequence protease PreP forms a unique 10,000 Angstroms3 chamber for proteolysis | journal = The EMBO Journal | volume = 25 | issue = 9 | pages = 1977–86 | date = May 2006 | pmid = 16601675 | pmc = 1456932 | doi = 10.1038/sj.emboj.7601080 }}</ref> It primarily localizes to the mitochondrial matrix, and cuts a range of peptides into recyclable fragments.<ref name="pmid21621546">{{cite journal | vauthors = Alikhani N, Berglund AK, Engmann T, Spånning E, Vögtle FN, Pavlov P, Meisinger C, Langer T, Glaser E | title = Targeting capacity and conservation of PreP homologues localization in mitochondria of different species | journal = Journal of Molecular Biology | volume = 410 | issue = 3 | pages = 400–10 | date = July 2011 | pmid = 21621546 | doi = 10.1016/j.jmb.2011.05.009 }}</ref><ref name="pmid19196155">{{cite journal | vauthors = Chow KM, Gakh O, Payne IC, Juliano MA, Juliano L, Isaya G, Hersh LB | title = Mammalian pitrilysin: substrate specificity and mitochondrial targeting | journal = Biochemistry | volume = 48 | issue = 13 | pages = 2868–77 | date = April 2009 | pmid = 19196155 | pmc = 2765508 | doi = 10.1021/bi8016125 }}</ref> The substrates of PreP are vital to proteostasis, as they can insert to mitochondrial membranes, disrupting [[electrical potential]] and uncoupling respiration.<ref name="pmid17562452">{{cite journal | vauthors = Koppen M, Langer T | title = Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 42 | issue = 3 | pages = 221–42 | date = 2007 | pmid = 17562452 | doi = 10.1080/10409230701380452 }}</ref><ref name="pmid22172993">{{cite journal | vauthors = Mossmann D, Meisinger C, Vögtle FN | title = Processing of mitochondrial presequences | journal = Biochimica et Biophysica Acta | volume = 1819 | issue = 9–10 | pages = 1098–106 | date = 2012 | pmid = 22172993 | doi = 10.1016/j.bbagrm.2011.11.007 }}</ref> Thus deletion of ''PRTRM1'' leads to a delayed growth phenotype.<ref name="pmid15772085">{{cite journal | vauthors = Kambacheld M, Augustin S, Tatsuta T, Müller S, Langer T | title = Role of the novel metallopeptidase Mop112 and saccharolysin for the complete degradation of proteins residing in different subcompartments of mitochondria | journal = The Journal of Biological Chemistry | volume = 280 | issue = 20 | pages = 20132–9 | date = May 2005 | pmid = 15772085 | doi = 10.1074/jbc.M500398200 }}</ref><ref name="pmid19701724">{{cite journal | vauthors = Nilsson Cederholm S, Bäckman HG, Pesaresi P, Leister D, Glaser E | title = Deletion of an organellar peptidasome PreP affects early development in Arabidopsis thaliana | journal = Plant Molecular Biology | volume = 71 | issue = 4–5 | pages = 497–508 | date = November 2009 | pmid = 19701724 | doi = 10.1007/s11103-009-9534-6 }}</ref> Notabley, PreP degrades several functionally relevant Aβ species, the aggregates of which are toxic to the [[neuron]] and play a key role in AD pathogenesis.<ref name="pmid21750375">{{cite journal | vauthors = Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS | title = Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria | journal = Journal of Alzheimer's Disease | volume = 27 | issue = 1 | pages = 75–87 | date = 2011 | pmid = 21750375 | pmc = 3381900 | doi = 10.3233/JAD-2011-101716 | hdl = 1808/17858 }}</ref><ref name="pmid16849325"/><ref name="pmid19962426">{{cite journal | vauthors = Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C | title = Genetic and biochemical studies of SNPs of the mitochondrial A beta-degrading protease, hPreP | journal = Neuroscience Letters | volume = 469 | issue = 2 | pages = 204–8 | date = January 2010 | pmid = 19962426 | doi = 10.1016/j.neulet.2009.11.075 }}</ref>


==Clinical significance==
==Clinical significance==


PreP is the Aβ-degrading protease in mitochondria. Immune-depletion of PreP in brain mitochondria prevents degradation of mitochondrial Aβ, and PreP activity is found diminished in AD patients.<ref name="pmid24931469"/> It has been reported that the loss of PreP activity is due to [[methionine]] oxidation and this study provides a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.<ref name="pmid25236746">{{cite journal | vauthors = Chen J, Teixeira PF, Glaser E, Levine RL | title = Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide | journal = Free Radical Biology & Medicine | volume = 77 | pages = 57–63 | date = December 2014 | pmid = 25236746 | doi = 10.1016/j.freeradbiomed.2014.08.016 | pmc=4258540}}</ref> A recent study also suggests that PreP regulates [[islet amyloid polypeptide]] in [[beta cells]].<ref name="pmid26191799">{{cite journal | vauthors = Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB | title = The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells | journal = PLoS One | volume = 10 | issue = 7 | pages = e0133263 | date = 2015 | pmid = 26191799 | doi = 10.1371/journal.pone.0133263 | pmc=4507941}}</ref>
PreP is the Aβ-degrading protease in mitochondria. Immune-depletion of PreP in brain mitochondria prevents degradation of mitochondrial Aβ, and PreP activity is found diminished in AD patients.<ref name="pmid24931469"/> It has been reported that the loss of PreP activity is due to [[methionine]] oxidation and this study provides a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.<ref name="pmid25236746">{{cite journal | vauthors = Chen J, Teixeira PF, Glaser E, Levine RL | title = Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide | journal = Free Radical Biology & Medicine | volume = 77 | pages = 57–63 | date = December 2014 | pmid = 25236746 | pmc = 4258540 | doi = 10.1016/j.freeradbiomed.2014.08.016 }}</ref> A recent study also suggests that PreP regulates [[islet amyloid polypeptide]] in [[beta cells]].<ref name="pmid26191799">{{cite journal | vauthors = Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB | title = The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells | journal = PLOS One | volume = 10 | issue = 7 | pages = e0133263 | date = 2015 | pmid = 26191799 | pmc = 4507941 | doi = 10.1371/journal.pone.0133263 }}</ref> Two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) were reported to be associated with an autosomal recessive, slowly progressive syndrome. Clinical features include mental retardation, spinocerebellar ataxia, cognitive decline and psychosis.<ref>{{cite journal | vauthors = Brunetti D, Torsvik J, Dallabona C, Teixeira P, Sztromwasser P, Fernandez-Vizarra E, Cerutti R, Reyes A, Preziuso C, D'Amati G, Baruffini E, Goffrini P, Viscomi C, Ferrero I, Boman H, Telstad W, Johansson S, Glaser E, Knappskog PM, Zeviani M, Bindoff LA | display-authors = 6 | title = Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration | journal = EMBO Molecular Medicine | volume = 8 | issue = 3 | pages = 176–90 | date = March 2016 | pmid = 26697887 | pmc = 4772954 | doi = 10.15252/emmm.201505894 }}</ref> A mouse model hemizygous for PITRM1 displayed progressive ataxia which was suggested to be linked to brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Recently, two brothers from a consanguineous family presenting with childhood-onset recessive cerebellar pathology were shown to carry a homozygous mutation in PITRM1 (c.2795C>T, p.T931M). This mutation resulted in 95% reduction in PITRM1 protein.<ref>{{cite journal | vauthors = Langer Y, Aran A, Gulsuner S, Abu Libdeh B, Renbaum P, Brunetti D, Teixeira PF, Walsh T, Zeligson S, Ruotolo R, Beeri R, Dweikat I, Shahrour M, Weinberg-Shukron A, Zahdeh F, Baruffini E, Glaser E, King MC, Levy-Lahad E, Zeviani M, Segel R | display-authors = 6 | title = PITRM1 peptidase loss-of-function in childhood cerebellar atrophy | journal = Journal of Medical Genetics | volume = 55 | issue = 9 | pages = jmedgenet–2018–105330 | date = May 2018 | pmid = 29764912 | doi = 10.1136/jmedgenet-2018-105330 }}</ref> PITRM1 knockdown was shown to lead to reduced levels of mature Frataxin protein,<ref>{{cite journal | vauthors = Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE | title = Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin | journal = Scientific Reports | volume = 5 | pages = 18251 | date = December 2015 | pmid = 26671574 | doi = 10.1038/srep18251 }}</ref> a protein that when deficient causes Friedreich's ataxia, and may be implicated in pathology in patients carrying PITRM1 mutations.


== Interactions ==
== Interactions ==
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== Model organisms ==
== Model organisms ==


[[Model organism]]s have been used in the study of PITRM1 function. A conditional [[knockout mouse]] line called ''Pitrm1<sup>tm1a(KOMP)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pitrm1#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref><ref name="pmid23870131">{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = July 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }}</ref> Additional screens performed:  - In-depth immunological phenotyping<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pitrm1&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>  
[[Model organism]]s have been used in the study of PITRM1 function. A conditional [[knockout mouse]] line called ''Pitrm1<sup>tm1a(KOMP)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice | vauthors = Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pitrm1#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = January 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref><ref name="pmid23870131">{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = July 2013 | pmid = 23870131 | pmc = 3717207 | doi = 10.1016/j.cell.2013.06.022 }}</ref> Additional screens performed:  - In-depth immunological phenotyping<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pitrm1&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>  
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|+ ''Pitrm1'' knockout mouse phenotype
|+ ''Pitrm1'' knockout mouse phenotype
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{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ | title = MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade | journal = Science | volume = 281 | issue = 5383 | pages = 1668–71 | date = September 1998 | pmid = 9733512 | doi = 10.1126/science.281.5383.1668 }}
* {{cite journal | vauthors = Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ | title = MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade | journal = Science | volume = 281 | issue = 5383 | pages = 1668–71 | date = September 1998 | pmid = 9733512 | doi = 10.1126/science.281.5383.1668 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
{{refend}}
{{refend}}

Latest revision as of 13:38, 7 November 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Wikidata
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Pitrilysin metallopeptidase 1 also known as presequence protease, mitochondrial (PreP) and metalloprotease 1 (MTP-1) is an enzyme that in humans is encoded by the PITRM1 gene.[1][2][3] It is also sometimes called metalloprotease 1 (MP1).PreP facilitates proteostasis by utilizing an ~13300-A(3) catalytic chamber to degrade toxic peptides, including mitochondrial presequences and β-amyloid.[4] Deficiency of PreP is found associated with Alzheimer’s disease. Reduced levels of PreP via RNAi mediated knockdown have been shown to lead to defective maturation of the protein Frataxin.[5]

Structure

Gene

The PITRM1 gene is located at chromosome 10q15.2, consisting of 28 exons.

Protein

PreP is a 117 kDa M16C enzyme that is widely expressed in human tissues.[6] PreP is composed of PreP-N (aa 33-509) and PreP-C (aa 576-1037) domains, which are connected by an extended helical hairpin (aa 510-575). Its structure demonstrates that substrate selection by size-exclusion is a conserved mechanism in M16C proteases.[4]

Function

PreP is an Zn2+-dependent and ATP-independent metalloprotease, it doesn’t select substrates on the basis of post-translational modifications or embedded degradation tags.[7][8][9] Instead, it uses a negatively charged catalytic chamber to engulf substrates peptides of up to ~65 residues while excluding larger, folded proteins.[10][11] It primarily localizes to the mitochondrial matrix, and cuts a range of peptides into recyclable fragments.[12][13] The substrates of PreP are vital to proteostasis, as they can insert to mitochondrial membranes, disrupting electrical potential and uncoupling respiration.[14][15] Thus deletion of PRTRM1 leads to a delayed growth phenotype.[16][17] Notabley, PreP degrades several functionally relevant Aβ species, the aggregates of which are toxic to the neuron and play a key role in AD pathogenesis.[18][10][19]

Clinical significance

PreP is the Aβ-degrading protease in mitochondria. Immune-depletion of PreP in brain mitochondria prevents degradation of mitochondrial Aβ, and PreP activity is found diminished in AD patients.[4] It has been reported that the loss of PreP activity is due to methionine oxidation and this study provides a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.[20] A recent study also suggests that PreP regulates islet amyloid polypeptide in beta cells.[21] Two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) were reported to be associated with an autosomal recessive, slowly progressive syndrome. Clinical features include mental retardation, spinocerebellar ataxia, cognitive decline and psychosis.[22] A mouse model hemizygous for PITRM1 displayed progressive ataxia which was suggested to be linked to brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Recently, two brothers from a consanguineous family presenting with childhood-onset recessive cerebellar pathology were shown to carry a homozygous mutation in PITRM1 (c.2795C>T, p.T931M). This mutation resulted in 95% reduction in PITRM1 protein.[23] PITRM1 knockdown was shown to lead to reduced levels of mature Frataxin protein,[24] a protein that when deficient causes Friedreich's ataxia, and may be implicated in pathology in patients carrying PITRM1 mutations.

Interactions

PITRM1 has been shown to interact with the following proteins: CCL22, CGB2, DDX41, DEFB104A, HDHD3, MRPL12, NDUFV2, PRDX6, PRKCSH, RARS2, RIF1, SUCLG2, TEKT3, TERF2, and VAPB.[25]

Model organisms

Model organisms have been used in the study of PITRM1 function. A conditional knockout mouse line called Pitrm1tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[26] Male and female animals underwent a standardized phenotypic screen[27] to determine the effects of deletion.[28][29][30][31] Additional screens performed: - In-depth immunological phenotyping[32]

References

  1. ↑ Marusov EV (July 1977). "[Ecological sterotypes of defensive behavior in fish under the action of chemical danger signals]". Nauchnye Doklady Vysshei Shkoly. Biologicheskie Nauki (8): 67–9. PMID 1036083.
  2. ↑ Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (June 1999). "Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (3): 197–205. doi:10.1093/dnares/6.3.197. PMID 10470851.
  3. ↑ "Entrez Gene: PITRM1 pitrilysin metallopeptidase 1".
  4. ↑ 4.0 4.1 4.2 King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ (July 2014). "Molecular basis of substrate recognition and degradation by human presequence protease". Structure. 22 (7): 996–1007. doi:10.1016/j.str.2014.05.003. PMC 4128088. PMID 24931469.
  5. ↑ Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE (December 2015). "Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin". Scientific Reports. 5 (1): 18251. doi:10.1038/srep18251. PMC 4680912. PMID 26671574.
  6. ↑ Mzhavia N, Berman YL, Qian Y, Yan L, Devi LA (May 1999). "Cloning, expression, and characterization of human metalloprotease 1: a novel member of the pitrilysin family of metalloendoproteases". DNA and Cell Biology. 18 (5): 369–80. doi:10.1089/104454999315268. PMID 10360838.
  7. ↑ Malito E, Hulse RE, Tang WJ (August 2008). "Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin". Cellular and Molecular Life Sciences. 65 (16): 2574–85. doi:10.1007/s00018-008-8112-4. PMC 2756532. PMID 18470479.
  8. ↑ Ravid T, Hochstrasser M (September 2008). "Diversity of degradation signals in the ubiquitin-proteasome system". Nature Reviews. Molecular Cell Biology. 9 (9): 679–90. doi:10.1038/nrm2468. PMC 2606094. PMID 18698327.
  9. ↑ Sauer RT, Baker TA (2011). "AAA+ proteases: ATP-fueled machines of protein destruction". Annual Review of Biochemistry. 80: 587–612. doi:10.1146/annurev-biochem-060408-172623. PMID 21469952.
  10. ↑ 10.0 10.1 Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E (September 2006). "Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP". The Journal of Biological Chemistry. 281 (39): 29096–104. doi:10.1074/jbc.M602532200. PMID 16849325.
  11. ↑ Johnson KA, Bhushan S, Ståhl A, Hallberg BM, Frohn A, Glaser E, Eneqvist T (May 2006). "The closed structure of presequence protease PreP forms a unique 10,000 Angstroms3 chamber for proteolysis". The EMBO Journal. 25 (9): 1977–86. doi:10.1038/sj.emboj.7601080. PMC 1456932. PMID 16601675.
  12. ↑ Alikhani N, Berglund AK, Engmann T, Spånning E, Vögtle FN, Pavlov P, Meisinger C, Langer T, Glaser E (July 2011). "Targeting capacity and conservation of PreP homologues localization in mitochondria of different species". Journal of Molecular Biology. 410 (3): 400–10. doi:10.1016/j.jmb.2011.05.009. PMID 21621546.
  13. ↑ Chow KM, Gakh O, Payne IC, Juliano MA, Juliano L, Isaya G, Hersh LB (April 2009). "Mammalian pitrilysin: substrate specificity and mitochondrial targeting". Biochemistry. 48 (13): 2868–77. doi:10.1021/bi8016125. PMC 2765508. PMID 19196155.
  14. ↑ Koppen M, Langer T (2007). "Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases". Critical Reviews in Biochemistry and Molecular Biology. 42 (3): 221–42. doi:10.1080/10409230701380452. PMID 17562452.
  15. ↑ Mossmann D, Meisinger C, Vögtle FN (2012). "Processing of mitochondrial presequences". Biochimica et Biophysica Acta. 1819 (9–10): 1098–106. doi:10.1016/j.bbagrm.2011.11.007. PMID 22172993.
  16. ↑ Kambacheld M, Augustin S, Tatsuta T, Müller S, Langer T (May 2005). "Role of the novel metallopeptidase Mop112 and saccharolysin for the complete degradation of proteins residing in different subcompartments of mitochondria". The Journal of Biological Chemistry. 280 (20): 20132–9. doi:10.1074/jbc.M500398200. PMID 15772085.
  17. ↑ Nilsson Cederholm S, Bäckman HG, Pesaresi P, Leister D, Glaser E (November 2009). "Deletion of an organellar peptidasome PreP affects early development in Arabidopsis thaliana". Plant Molecular Biology. 71 (4–5): 497–508. doi:10.1007/s11103-009-9534-6. PMID 19701724.
  18. ↑ Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS (2011). "Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria". Journal of Alzheimer's Disease. 27 (1): 75–87. doi:10.3233/JAD-2011-101716. hdl:1808/17858. PMC 3381900. PMID 21750375.
  19. ↑ Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C (January 2010). "Genetic and biochemical studies of SNPs of the mitochondrial A beta-degrading protease, hPreP". Neuroscience Letters. 469 (2): 204–8. doi:10.1016/j.neulet.2009.11.075. PMID 19962426.
  20. ↑ Chen J, Teixeira PF, Glaser E, Levine RL (December 2014). "Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide". Free Radical Biology & Medicine. 77: 57–63. doi:10.1016/j.freeradbiomed.2014.08.016. PMC 4258540. PMID 25236746.
  21. ↑ Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB (2015). "The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells". PLOS One. 10 (7): e0133263. doi:10.1371/journal.pone.0133263. PMC 4507941. PMID 26191799.
  22. ↑ Brunetti D, Torsvik J, Dallabona C, Teixeira P, Sztromwasser P, Fernandez-Vizarra E, et al. (March 2016). "Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration". EMBO Molecular Medicine. 8 (3): 176–90. doi:10.15252/emmm.201505894. PMC 4772954. PMID 26697887.
  23. ↑ Langer Y, Aran A, Gulsuner S, Abu Libdeh B, Renbaum P, Brunetti D, et al. (May 2018). "PITRM1 peptidase loss-of-function in childhood cerebellar atrophy". Journal of Medical Genetics. 55 (9): jmedgenet–2018–105330. doi:10.1136/jmedgenet-2018-105330. PMID 29764912.
  24. ↑ Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE (December 2015). "Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin". Scientific Reports. 5: 18251. doi:10.1038/srep18251. PMID 26671574.
  25. ↑ "PITRM1 interaction network". BioGRID. Retrieved 6 August 2016.
  26. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  27. ↑ 27.0 27.1 "International Mouse Phenotyping Consortium".
  28. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  29. ↑ Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  30. ↑ Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  31. ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (July 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  32. ↑ 32.0 32.1 "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

  • Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ (September 1998). "MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade". Science. 281 (5383): 1668–71. doi:10.1126/science.281.5383.1668. PMID 9733512.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
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