PITRM1 explained

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 does not 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]

Further reading

Notes and References

  1. Marusov EV . [Ecological sterotypes of defensive behavior in fish under the action of chemical danger signals] . Nauchnye Doklady Vysshei Shkoly. Biologicheskie Nauki . 8 . 67–9 . July 1977 . 1036083 .
  2. Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 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 . June 1999 . 10470851 . 10.1093/dnares/6.3.197 . free .
  3. Web site: Entrez Gene: PITRM1 pitrilysin metallopeptidase 1.
  4. King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ . Molecular basis of substrate recognition and degradation by human presequence protease . Structure . 22 . 7 . 996–1007 . July 2014 . 24931469 . 4128088 . 10.1016/j.str.2014.05.003 .
  5. Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE . Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin . Scientific Reports . 5 . 1 . 18251 . December 2015 . 26671574 . 4680912 . 10.1038/srep18251 . 2015NatSR...518251N .
  6. Mzhavia N, Berman YL, Qian Y, Yan L, Devi LA . 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 . May 1999 . 10360838 . 10.1089/104454999315268 .
  7. Malito E, Hulse RE, Tang WJ . Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin . Cellular and Molecular Life Sciences . 65 . 16 . 2574–85 . August 2008 . 18470479 . 2756532 . 10.1007/s00018-008-8112-4 .
  8. Ravid T, Hochstrasser M . Diversity of degradation signals in the ubiquitin-proteasome system . Nature Reviews. Molecular Cell Biology . 9 . 9 . 679–90 . September 2008 . 18698327 . 2606094 . 10.1038/nrm2468 .
  9. Sauer RT, Baker TA . AAA+ proteases: ATP-fueled machines of protein destruction . Annual Review of Biochemistry . 80 . 587–612 . 2011 . 21469952 . 10.1146/annurev-biochem-060408-172623 .
  10. Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E . Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP . The Journal of Biological Chemistry . 281 . 39 . 29096–104 . September 2006 . 16849325 . 10.1074/jbc.M602532200 . free .
  11. Johnson KA, Bhushan S, Ståhl A, Hallberg BM, Frohn A, Glaser E, Eneqvist T . The closed structure of presequence protease PreP forms a unique 10,000 Angstroms3 chamber for proteolysis . The EMBO Journal . 25 . 9 . 1977–86 . May 2006 . 16601675 . 1456932 . 10.1038/sj.emboj.7601080 .
  12. Alikhani N, Berglund AK, Engmann T, Spånning E, Vögtle FN, Pavlov P, Meisinger C, Langer T, Glaser E . Targeting capacity and conservation of PreP homologues localization in mitochondria of different species . Journal of Molecular Biology . 410 . 3 . 400–10 . July 2011 . 21621546 . 10.1016/j.jmb.2011.05.009 .
  13. Chow KM, Gakh O, Payne IC, Juliano MA, Juliano L, Isaya G, Hersh LB . Mammalian pitrilysin: substrate specificity and mitochondrial targeting . Biochemistry . 48 . 13 . 2868–77 . April 2009 . 19196155 . 2765508 . 10.1021/bi8016125 .
  14. Koppen M, Langer T . Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases . Critical Reviews in Biochemistry and Molecular Biology . 42 . 3 . 221–42 . 2007 . 17562452 . 10.1080/10409230701380452 . 6819247 .
  15. Mossmann D, Meisinger C, Vögtle FN . Processing of mitochondrial presequences . Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms . 1819 . 9–10 . 1098–106 . 2012 . 22172993 . 10.1016/j.bbagrm.2011.11.007 .
  16. Kambacheld M, Augustin S, Tatsuta T, Müller S, Langer T . 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 . May 2005 . 15772085 . 10.1074/jbc.M500398200 . free .
  17. Nilsson Cederholm S, Bäckman HG, Pesaresi P, Leister D, Glaser E . Deletion of an organellar peptidasome PreP affects early development in Arabidopsis thaliana . Plant Molecular Biology . 71 . 4–5 . 497–508 . November 2009 . 19701724 . 10.1007/s11103-009-9534-6 . 28627753 .
  18. Alikhani N, Guo L, Yan S, Du H, Pinho CM, Chen JX, Glaser E, Yan SS . 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 . 2011 . 21750375 . 3381900 . 10.3233/JAD-2011-101716 . 1808/17858 .
  19. Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C . Genetic and biochemical studies of SNPs of the mitochondrial A beta-degrading protease, hPreP . Neuroscience Letters . 469 . 2 . 204–8 . January 2010 . 19962426 . 10.1016/j.neulet.2009.11.075 . 31073898 .
  20. Chen J, Teixeira PF, Glaser E, Levine RL . Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide . Free Radical Biology & Medicine . 77 . 57–63 . December 2014 . 25236746 . 4258540 . 10.1016/j.freeradbiomed.2014.08.016 .
  21. Guan H, Chow KM, Song E, Verma N, Despa F, Hersh LB . The Mitochondrial Peptidase Pitrilysin Degrades Islet Amyloid Polypeptide in Beta-Cells . PLOS ONE . 10 . 7 . e0133263 . 2015 . 26191799 . 4507941 . 10.1371/journal.pone.0133263 . free . 2015PLoSO..1033263G .
  22. 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 . Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration . EMBO Molecular Medicine . 8 . 3 . 176–90 . March 2016 . 26697887 . 4772954 . 10.15252/emmm.201505894 .
  23. 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 . PITRM1 peptidase loss-of-function in childhood cerebellar atrophy . Journal of Medical Genetics . 55 . 9 . jmedgenet–2018–105330 . May 2018 . 29764912 . 10.1136/jmedgenet-2018-105330 . 2434/622800 . 21727945 . free .
  24. Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE . Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin . Scientific Reports . 5 . 18251 . December 2015 . 26671574 . 10.1038/srep18251 . 4680912 . 2015NatSR...518251N .
  25. Web site: PITRM1 interaction network . . 6 August 2016 .

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