Wikipedia

PITRM1

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

10531

69617

Ensembl

ENSG00000107959

ENSMUSG00000021193

UniProt

Q5JRX3

Q8K411

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

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Aminokiselinska sekvenca

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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
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Gen

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

Protein

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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

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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

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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

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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

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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

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  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.
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  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.
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Dopunska literatura

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  • 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

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Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=PITRM1&oldid=3673253"