Pitrilizin-metalopeptidaza 1, znana i kao mitohondrijska presekvencna proteaza, (PreP) i metaloproteaza 1 (MTP-1) je enzim koji je kod ljudi kodiran genom PITRM1.[5][6][7] Ponekad se naziva i metaloproteaza 1 (MP1). PreP olakšava proteostazu korištenjem katalitske komore od ~13300-A (3) za razgradnju toksičnih peptida, uključujući mitohondrijske posljedice i β-amiloid.[8] Nedostatak PreP-a je povezan s Alzheimerovom bolešću. Pokazalo se da smanjeni nivoi PreP-a putem nokdauna posredovane RNK dovode do defektnog sazrijevanja proteina frataksina.[9]

PITRM1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4L3T, 4NGE, 4RPU

Identifikatori
AliasiPITRM1
Vanjski ID-jeviOMIM: 618211 MGI: 1916867 HomoloGene: 5742 GeneCards: PITRM1
Lokacija gena (čovjek)
Hromosom 10 (čovjek)
Hrom.Hromosom 10 (čovjek)[1]
Hromosom 10 (čovjek)
Genomska lokacija za PITRM1
Genomska lokacija za PITRM1
Bend10p15.2Početak3,137,728 bp[1]
Kraj3,172,841 bp[1]
Lokacija gena (miš)
Hromosom 13 (miš)
Hrom.Hromosom 13 (miš)[2]
Hromosom 13 (miš)
Genomska lokacija za PITRM1
Genomska lokacija za PITRM1
Bend13|13 A1Početak6,598,185 bp[2]
Kraj6,630,551 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija GO:0070122 peptidase activity
GO:0010577 enzyme activator activity
catalytic activity
hydrolase activity
vezivanje iona metala
metallopeptidase activity
metalloendopeptidase activity
vezivanje iona cinka
Ćelijska komponenta mitohondrija
mitochondrial matrix
Biološki proces GO:0048554 positive regulation of catalytic activity
protein targeting to mitochondrion
Proteoliza
protein processing
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001242307
NM_001242309
NM_014889
NM_014968
NM_001347725

NM_001347726
NM_001347727
NM_001347728
NM_001347729
NM_001347730

NM_145131
NM_001360106

RefSeq (bjelančevina)
NP_001229236
NP_001229238
NP_001334654
NP_001334655
NP_001334656

NP_001334657
NP_001334658
NP_001334659
NP_055704

NP_660113
NP_001347035

Lokacija (UCSC)Chr 10: 3.14 – 3.17 MbChr 13: 6.6 – 6.63 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Struktura

uredi

Aminokiselinska sekvenca

uredi

Dužina polipeptidnog lanca je 1.037 aminokiselina, а molekulska težina 117.413 Da.[10]

1020304050
MWRCGGRQGLCVLRRLSGGHAHHRAWRWNSNRACERALQYKLGDKIHGFT
VNQVTSVPELFLTAVKLTHDDTGARYLHLAREDTNNLFSVQFRTTPMDST
GVPHILEHTVLCGSQKYPCRDPFFKMLNRSLSTFMNAFTASDYTLYPFST
QNPKDFQNLLSVYLDATFFPCLRELDFWQEGWRLEHENPSDPQTPLVFKG
VVFNEMKGAFTDNERIFSQHLQNRLLPDHTYSVVSGGDPLCIPELTWEQL
KQFHATHYHPSNARFFTYGNFPLEQHLKQIHEEALSKFQKIEPSTVVPAQ
TPWDKPREFQITCGPDSFATDPSKQTTISVSFLLPDITDTFEAFTLSLLS
SLLTSGPNSPFYKALIESGLGTDFSPDVGYNGYTREAYFSVGLQGIAEKD
IETVRSLIDRTIDEVVEKGFEDDRIEALLHKIEIQMKHQSTSFGLMLTSY
IASCWNHDGDPVELLKLGNQLAKFRQCLQENPKFLQEKVKQYFKNNQHKL
TLSMRPDDKYHEKQAQVEATKLKQKVEALSPGDRQQIYEKGLELRSQQSK
PQDASCLPALKVSDIEPTIPVTELDVVLTAGDIPVQYCAQPTNGMVYFRA
FSSLNTLPEELRPYVPLFCSVLTKLGCGLLDYREQAQQIELKTGGMSASP
HVLPDDSHMDTYEQGVLFSSLCLDRNLPDMMQLWSEIFNNPCFEEEEHFK
VLVKMTAQELANGIPDSGHLYASIRAGRTLTPAGDLQETFSGMDQVRLMK
RIAEMTDIKPILRKLPRIKKHLLNGDNMRCSVNATPQQMPQTEKAVEDFL
RSIGRSKKERRPVRPHTVEKPVPSSSGGDAHVPHGSQVIRKLVMEPTFKP
WQMKTHFLMPFPVNYVGECIRTVPYTDPDHASLKILARLMTAKFLHTEIR
EKGGAYGGGAKLSHNGIFTLYSYRDPNTIETLQSFGKAVDWAKSGKFTQQ
DIDEAKLSVFSTVDAPVAPSDKGMDHFLYGLSDEMKQAHREQLFAVSHDK
LLAVSDRYLGTGKSTHGLAILGPENPKIAKDPSWIIQ

Gen PITRM1 nalazi se na hromosomu 10, sekvenca q15.2, a sastoji se od 28 egzona.

Protein

uredi

PreP je 117 kDa M16C enzim koji je široko eksprimiran u ljudskim tkivima.[11] PreP se sastoji od PreP-N (aa 33-509) i PreP-C (aa 576-1037) domena, koji su povezani produženim spiralom ukosnica (aa 510 -575). Njegova struktura pokazuje da je odabir supstrata isključivanjem veličine konzervirani mehanizam u M16C proteazama.[8]

Funkcija

uredi

PreP je Zn2+-ovisna i ATP-neovisna metaloproteaza, it doesn’t select substrates on the basis of post-translational modifications or embedded degradation tags.[12][13][14] Umjesto toga, koristi negativno nabijenu katalitsku komoru, kako bi zahvatio supstrate peptida do ~65 ostataka, isključujući veće, savijene proteine.[15][16] Primarno je lokaliziran u mitohondrijskom matriksu, gdje cijepa peptide u reciklibilne fragmente.[17][18] Ne bira podloge na temelju posttranslacijskih modifikacija ili ugrađenih oznaka razgradnje.[19][20] Stoga delecija PRTRM1 dovodi do odgođenog fenotipa rasta.[21][22] Značajno je da PreP razgrađuje nekoliko funkcionalno relevantnih tipova β, čiji su agregati toksični za neurone i imaju ključnu ulogu u patogenezi Alzheimerove bolesti (AD).[15][23][24]

Klinički značaj

uredi

PreP je proteaza koja razgrađuje Aβ u mitohondrijama. Imuno-iscrpljivanje PreP-a u moždanim mitohondrijama sprječava razgradnju mitohondrijskog Ap, a utvrđeno je da je aktivnost PreP-a smanjena kod pacijenata s AD.[8] Prijavljeno je da je gubitak PreP aktivnosti posljedica oksidacije metionina i ovo istraživanje pruža racionalnu osnovu za terapijsku intervenciju u stanjima karakteriziranim prekomjernom oksidacijom PreP-a.[25] Nedavna studija također sugerira da PreP regulira amiloidne polipeptidne otočiće u beta-ćelijama.[26] Za dva brata i sestre koji nose homozigotnu PITRM1 misens mutaciju (c.548G> A, p.Arg183Gln) prijavljeno je da su povezani s autosomno recesivnim, sporo progresivnim sindromom. Kliničke značajke uključuju mentalnu retardaciju, spinocerebelarnu ataksiju, kognitivni pad i psihozu.[27] Hemizigotni model miša za PITRM1 pokazao je progresivnu ataksiju za koju se pretpostavljalo da je povezana s degenerativnim lezijama mozga, uključujući nakupljanje Aβ-pozitivnih amiloidnih naslaga. Nedavno je pokazano da dva brata iz srodničke porodice sa recesivnom cerebelumskom patologijom u djetinjstvu nose homozigotnu mutaciju u PITRM1 (c.2795C > T, p.T931M). Ova mutacija je rezultirala je smanjenjem proteina PITRM1 za 95%.[28] Pokazalo se da nokdaun PITRM1 dovodi do smanjenja nivoa zrelog proteina frataksina,[29] protein čiji nedostatk uzrokuje Friedreichovu ataksiju i može biti uključen u patološke promjene kod pacijenata koji nose PITRM1 mutacije.

Interakcije

uredi

Pokazano je da PITRM1 stupa u interakciju sa sljedećim proteinima: CCL22, CGB2, DDX41, DEFB104A, HDHD3, MRPL12, NDUFV2, PRDX6, PRKCSH, RARS2, RIF1, SUCLG2, TEKT3 , TERF2 i VAPB.[30]

Modelni organizmi

uredi

U proučavanju funkcije PITRM1 korišteni su i modelni organizmi. Uslovna linija nokaut-miša pod nazivom Pitrm1tm1a(KOMP)Wtsi generirana je u Wellcome Trust Sanger Institute.[31] Mužjaci i ženke podvrgnuti su standardiziranom fenotipskom pregledu[32] to determine the effects of deletion.[33][34][35][36] Izvršeni su dodatni pregledi: dubinsko imunsko fenotipiziranje.[37]

Fenotip nokaut-mišaPitrm1
Svojstvo Fenotip
Svi podaci raspoloživi su na linku.[32][37]
Limfociti periferne krvi 6 sedmica Normalan
Hematologija 6 sedmica Nenormalan
Insulin Normalan
Vijabilnost homozigota na P14 Nenormalan
Studija recesivne letalnosti Nenormalan
Tjelesna težina Normalan
Neurološka procjena Normalan
Snaga stiska Normalan
Dismorfologija Normalan
Indirektna kalorimetrija Normalan
Test tolerancije glukoze Normalan
Slušni odgovor možanog stabla Normalan
DEXA Normalan
Radiografija Normalan
Morfologija oka Normalan
Klinička hemija Normalan
Hematologija 16 sedmica Normalan
Leukociti periferne krvi 16 sedmica Normalan
Težina srca Normalan
Salmonella infekcija Normalan
Funkcija citotoksičnih T-ćelija Normalan
Slezena Normalan
Imunofenotipizacija mezenternih limfnih čvorova Normalna
Imunofenotipizacija koštane srži Normalan
Epidermni imunski sastav Normalan
Trichuris-ni izazov Normalan

Reference

uredi
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000107959 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021193 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Marusov EV (juli 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.
  6. ^ Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (juni 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.
  7. ^ "Entrez Gene: PITRM1 pitrilysin metallopeptidase 1".
  8. ^ a b c King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ (juli 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.
  9. ^ Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE (decembar 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.
  10. ^ "UniProt, Q5JRX3". Pristupljeno 4. 9. 2021.
  11. ^ Mzhavia N, Berman YL, Qian Y, Yan L, Devi LA (maj 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.
  12. ^ 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.
  13. ^ Ravid T, Hochstrasser M (septembar 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.
  14. ^ 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.
  15. ^ a b Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E (septembar 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.
  16. ^ Johnson KA, Bhushan S, Ståhl A, Hallberg BM, Frohn A, Glaser E, Eneqvist T (maj 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.
  17. ^ Alikhani N, Berglund AK, Engmann T, Spånning E, Vögtle FN, Pavlov P, Meisinger C, Langer T, Glaser E (juli 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.
  18. ^ 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.
  19. ^ 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. S2CID 6819247.
  20. ^ Mossmann D, Meisinger C, Vögtle FN (2012). "Processing of mitochondrial presequences". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1819 (9–10): 1098–106. doi:10.1016/j.bbagrm.2011.11.007. PMID 22172993.
  21. ^ Kambacheld M, Augustin S, Tatsuta T, Müller S, Langer T (maj 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.
  22. ^ Nilsson Cederholm S, Bäckman HG, Pesaresi P, Leister D, Glaser E (novembar 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. S2CID 28627753.
  23. ^ 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.
  24. ^ Pinho CM, Björk BF, Alikhani N, Bäckman HG, Eneqvist T, Fratiglioni L, Glaser E, Graff C (januar 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. S2CID 31073898.
  25. ^ Chen J, Teixeira PF, Glaser E, Levine RL (decembar 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.
  26. ^ 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.
  27. ^ Brunetti D, Torsvik J, Dallabona C, Teixeira P, Sztromwasser P, Fernandez-Vizarra E, et al. (mart 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.
  28. ^ Langer Y, Aran A, Gulsuner S, Abu Libdeh B, Renbaum P, Brunetti D, et al. (maj 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. S2CID 21727945.
  29. ^ Nabhan JF, Gooch RL, Piatnitski Chekler EL, Pierce B, Bulawa CE (decembar 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. PMC 4680912. PMID 26671574.
  30. ^ "PITRM1 interaction network". BioGRID. Pristupljeno 6. 8. 2016.
  31. ^ 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. S2CID 85911512.
  32. ^ a b "International Mouse Phenotyping Consortium".
  33. ^ 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 (juni 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.
  34. ^ Dolgin E (juni 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  35. ^ Collins FS, Rossant J, Wurst W (januar 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
  36. ^ 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 (juli 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.
  37. ^ a b "Infection and Immunity Immunophenotyping (3i) Consortium".[mrtav link]

Dopunska literatura

uredi
  • Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ (septembar 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 (oktobar 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 (januar 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.

Vanjski linkovi

uredi