PINK1

PINK1
Identifikatori
Aliasi	PINK1
Vanjski ID-jevi	OMIM: 608309 MGI: 1916193 HomoloGene: 32672 GeneCards: PINK1
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	20,651,511 bp
Lokacija gena (miš)
Hrom.	Hromosom 4 (miš)
Kraj	138,053,618 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• C3HC4-type RING finger domain binding; • kinase activity; • ATP binding; • protein kinase activity; • vezivanje iona metala; • protein serine/threonine kinase activity; • calcium-dependent protein kinase activity; • peptidase activator activity; • magnesium ion binding; • aktivnost sa transferazom; • protease binding; • GO:0001948, GO:0016582 vezivanje za proteine; • nucleotide binding; • protein kinase B binding; • ubiquitin protein ligase binding;
Ćelijska komponenta	• citoplazma; • citosol; • membrana; • mitochondrial intermembrane space; • mitohondrija; • perinuklearno područje citoplazme; • citoskelet; • jedro; • Lewy body; • integral component of mitochondrial outer membrane; • mitochondrial outer membrane; • Hromatin; • TORC2 complex; • integral component of membrane; • kompleks ubikvitin-ligaze; • Translokaza vanjske membrane; • astrocyte projection; • Akson; • cell body; • mitochondrial inner membrane; • growth cone;
Biološki proces	• GO:1904089 negative regulation of neuron apoptotic process; • positive regulation of mitophagy in response to mitochondrial depolarization; • positive regulation of free ubiquitin chain polymerization; • regulation of protein ubiquitination; • cellular response to toxic substance; • positive regulation of catecholamine secretion; • regulation of synaptic vesicle transport; • positive regulation of translation; • protein phosphorylation; • positive regulation of dopamine secretion; • macroautophagy; • GO:0106159 regulation of protein-containing complex assembly; • cellular response to hypoxia; • negative regulation of autophagosome assembly; • positive regulation of protein kinase B signaling; • positive regulation of protein dephosphorylation; • ubiquitin-dependent protein catabolic process; • peptidyl-serine autophosphorylation; • regulation of neuron apoptotic process; • GO:0001306 response to oxidative stress; • negative regulation of gene expression; • positive regulation of peptidyl-serine phosphorylation; • negative regulation of mitochondrial fission; • positive regulation of mitochondrial electron transport, NADH to ubiquinone; • positive regulation of macroautophagy; • regulation of autophagy of mitochondrion; • positive regulation of ubiquitin-protein transferase activity; • negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway; • protein ubiquitination; • negative regulation of oxidative stress-induced cell death; • negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide; • positive regulation of synaptic transmission, dopaminergic; • negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; • regulation of oxidative phosphorylation; • regulation of mitochondrion organization; • regulation of hydrogen peroxide metabolic process; • negative regulation of oxidative stress-induced neuron death; • protein stabilization; • mitochondrion organization; • positive regulation of DNA-binding transcription factor activity; • negative regulation of autophagy of mitochondrion; • GO:1904489 regulation of reactive oxygen species metabolic process; • positive regulation of ATP biosynthetic process; • maintenance of protein location in mitochondrion; • regulation of protein targeting to mitochondrion; • positive regulation of release of cytochrome c from mitochondria; • respiratory electron transport chain; • positive regulation of protein ubiquitination; • regulation of proteasomal protein catabolic process; • activation of protein kinase B activity; • GO:0007243 intracellular signal transduction; • negative regulation of macroautophagy; • positive regulation of protein targeting to mitochondrion; • positive regulation of cristae formation; • positive regulation of peptidase activity; • TORC2 signaling; • regulation of mitochondrial membrane potential; • Autofagija; • negative regulation of JNK cascade; • establishment of protein localization to mitochondrion; • autophagy of mitochondrion; • GO:0035404 peptidyl-serine phosphorylation; • positive regulation of I-kappaB kinase/NF-kappaB signaling; • cellular response to oxidative stress; • negative regulation of reactive oxygen species metabolic process; • negative regulation of apoptotic process; • positive regulation of protein phosphorylation; • positive regulation of histone deacetylase activity; • mitochondrion to lysosome transport; • regulation of cellular response to oxidative stress; • response to ischemia; • positive regulation of mitochondrial fission; • positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization; • cellular response to hydrogen sulfide; • Fosforilacija; • negative regulation of neuron death; • positive regulation of NMDA glutamate receptor activity; • negative regulation of intrinsic apoptotic signaling pathway;
	Izvori:Amigo / QuickGO
Ortolozi
	65018
	68943
	ENSG00000158828
	ENSMUSG00000028756
	Q9BXM7
	Q99MQ3
	NM_032409
	NM_026880
	NP_115785
	NP_081156
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

PTEN-inducirana kinaza 1 (PINK1) jest enzim koji je kod ljudi kodiran genom PINK1 sa hromosoma 1. To je mitohondrijska serin/treonin-specifična protein-kinaza .^[5]^[6]

Smatra se da štiti ćelije od disfunkcije mitohondrija izazvane stresom. PINK1 aktivnost uzrokuje parkin protein da se veže za depolarizirane mitohondrije, kako bi inducirao autofagiju tih mitohondrija.^[7]^[8] PINK1 se prerađuje u zdravim mitohondrijama i oslobađa da pokrene diferencijaciju neurona.^[9] Mutacije ovog gena uzrokuju jedan oblik ranog početka autosomno recesivnog oblkika Parkionsonove bolesti.^[10]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 581 aminokiselina, a molekulska težina 62.769 Da.^[11]

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

10	20	30	40	50
MAVRQALGRG	LQLGRALLLR	FTGKPGRAYG	LGRPGPAAGC	VRGERPGWAA
GPGAEPRRVG	LGLPNRLRFF	RQSVAGLAAR	LQRQFVVRAW	GCAGPCGRAV
FLAFGLGLGL	IEEKQAESRR	AVSACQEIQA	IFTQKSKPGP	DPLDTRRLQG
FRLEEYLIGQ	SIGKGCSAAV	YEATMPTLPQ	NLEVTKSTGL	LPGRGPGTSA
PGEGQERAPG	APAFPLAIKM	MWNISAGSSS	EAILNTMSQE	LVPASRVALA
GEYGAVTYRK	SKRGPKQLAP	HPNIIRVLRA	FTSSVPLLPG	ALVDYPDVLP
SRLHPEGLGH	GRTLFLVMKN	YPCTLRQYLC	VNTPSPRLAA	MMLLQLLEGV
DHLVQQGIAH	RDLKSDNILV	ELDPDGCPWL	VIADFGCCLA	DESIGLQLPF
SSWYVDRGGN	GCLMAPEVST	ARPGPRAVID	YSKADAWAVG	AIAYEIFGLV
NPFYGQGKAH	LESRSYQEAQ	LPALPESVPP	DVRQLVRALL	QREASKRPSA
RVAANVLHLS	LWGEHILALK	NLKLDKMVGW	LLQQSAATLL	ANRLTEKCCV
ETKMKMLFLA	NLECETLCQA	ALLLCSWRAA	L

Struktura

PINK1 se sintetizira kao protein od 63000 Da koji se često cijepa pomoću PARL, između ostataka 103-alanina i 104-fenilalanina, u fragment od 53.000 Da.^[12] PINK1 sadrži N-terminalnu sekvencu na mitohondrijama, pretpostavljenu transmembransku sekvencu, domen Ser/Thr kinaze i C-terminalnu regulatornu sekvencu. Utvrđeno je da se protein nalazi na vanjskoj membrani mitohondrija, ali se također može naći u cijelom citosolu. Eksperimenti sugeriraju da je domen Ser/Thr kinaze okrenut prema van prema citosolu, što ukazuje na moguću tačku interakcije s parkinom.^[13]

Struktura PINK1 je riješena i pokazuje kako protein veže i fosforilira svoj supstrat ubikvitin.^[14]

Funkcija

PINK1 je blisko uključen u kontrolu kvaliteta mitohondrija, tako što identifikuje oštećene mitohondrije i cilja specifične za degradaciju. Zdrave mitohondrije održavaju membranski potencijal koji se može koristiti za import PINK1 u unutrašnju membranu, gdje ga PARL cijepa i čisti od vanjske membrane. Jako oštećene mitohondrije nemaju dovoljan membranski potencijal za unos PINK1, koji se zatim akumulira na vanjskoj membrani. PINK1 zatim regrutuje parkin da cilja oštećene mitohondrije za degradaciju putem autofagija.^[15] Zbog prisustva PINK1 u cijeloj citoplazmi, sugerirano je da PINK1 funkcionira kao "izviđač" za ispitivanje oštećenih mitohondrija.^[16]

PINK1 prepoznaje oštećenu mitohondriju. Nakuplja se na vanjskoj membrani mitohondrija i regrutuje parkin. PINK1/parkin put tada označava mitohondrije za razgradnju u lizosomima.

Zdrave mitohondrije mogu da imoortuju PINK1 gde ga PARL potom cijepa. Ovo sprečava bilo kakvo nakupljanje PINK1 i parkin se ne regrutuje u mitohondrije.

PINK1 također može da kontrolira kvalitet mitohondrija putem mitohondrijske fisije. Time stvara se određeni broj kćeri mitohondrija, često s neravnomjernom raspodjelom u membranskom potencijalu. Vjerovatnije je da će mitohondrije sa jakim, zdravim membranskim potencijalom biti podvrgnute fuziji nego mitohondrije s niskim membranskim potencijalom. Interferencija s mitohondrijskim fisijskim putem dovela je do povećanja oksidiranih proteina i smanjenja disanja.^[17] Bez PINK1, parkin se ne može efikasno lokalizirati na oštećene mitohondrije, dok prekomjerna ekspresija PINK1 uzrokuje da se parkin lokalizira čak i na zdravim mitohondrijama.^[18] Nadalje, mutacije u Drp1, mitohondrijskom faktoru fisije i PINK1 bile su fatalne u Drosophila modelima. Međutim, prekomjerna ekspresija Drp1 mogla bi spasiti subjekte s nedostatkom PINK1 ili parkina, što sugerira da fisija mitohondrija koju je pokrenuo Drp1 rekreira iste efekte PINK1/parkin puta.^[19]

Pored fisije mitohondrija, PINK1 je uključen u njihovu pokretljivost. Akumulacija PINK1 i regrutovanje parkina cilja mitohondrije za degradaciju, a PINK1 može poslužiti za povećanje stope degradacije, zaustavljanjem pokretljivosti mitohondrija. Prekomjerna ekspresija PINK1 proizvela je slične efekte kao i utišavanje Miro-a, proteina blisko povezanog s mitohondrijskom migracijom.^[20]

Drugi mehanizam kontrole kvaliteta mitohondrija može nastati putem vezikula, izvedenih iz mitohondrija. Oksidativni stres u mitohondrijama može proizvesti potencijalno štetne spojeve, uključujući nepropisno presavijene proteine ili reaktivne vrste kisika. Pokazalo se da PINK1 olakšava stvaranje vezikula izvedenih iz mitohondrija, koje mogu odvojiti reaktivne vrste kisika i prebaciti ih prema lizosomima radi razgradnje.^[21]

Klinički značaj

Parkinsonovu bolest često karakteriše degeneracija dopaminskih neurona i povezana je sa nagomilavanjem nepropisno presavijenih proteina i Lewyjevih tijela. Pokazalo se da mutacije u PINK1 proteinu dovode do nakupljanja takvih nepropisno presavijenih proteina u mitohondrijama mišjih i ljudskih ćelija.^[22] Konkretno, mutacije u domenu serin/treonin kinaze pronađene su kod brojnih pacijenata oboljelih od Parkinsonove bolesti kod kojih PINK1 ne uspijeva zaštititi od stresom izazvane mitohondrijske disfunkcije i apoptoze.^[23]

Farmakološka manipulacija

Do danas je bilo nekoliko izvještaja o malim molekulama koje aktiviraju PINK1 i njihovo obećavajuće djelovanje kao potencijalnog tretmana za Parkinsonovu bolest. Prvi izvještaj pojavio se 2013. godine kada su Kevan Shokat i njegov tim iz UCSF identificirali nukleobazu zvanu kinetin kao aktivator PINK1.^[24] Kasnije su drugi pokazali da nukleozidni derivat kinetina, tj. kinetin ribozid, pokazuje značajnu aktivaciju PINK1 u ćelijama.^[25] Osim toga, monofosfatni prolijekovi kinetin-ribozida, ProTides, također su pokazali aktivaciju PINK1.^[25] U decembru 2017., niklozamid, anthelmintski lijek, identificiran je kao snažan aktivator PINK1 u ćelijama i neuronima.^[26]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000158828 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000028756 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Unoki M, Nakamura Y (Aug 2001). "Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway". Oncogene. 20 (33): 4457–65. doi:10.1038/sj.onc.1204608. PMID 11494141.
^ Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR (Sep 2004). "PINK1 mutations are associated with sporadic early-onset parkinsonism". Ann Neurol. 56 (3): 336–41. doi:10.1002/ana.20256. PMID 15349860. S2CID 11049051.
^ Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010). "PINK1 is selectively stabilized on impaired mitochondria to activate Parkin". PLOS Biology. 8 (1): e1000298. doi:10.1371/journal.pbio.1000298. PMC 2811155. PMID 20126261.
^ Lazarou M, Narendra DP, Jin SM, Tekle E, Banerjee S, Youle RJ (2013). "PINK1 drives Parkin self-association and HECT-like E3 activity upstream of mitochondrial binding". Journal of Cell Biology. 200 (2): 163–172. doi:10.1083/jcb.201210111. PMC 3549971. PMID 23319602.
^ Dagda RK, Pien I, Wang R, Zhu J, Wang KZ, Callio J, Banerjee TD, Dagda RY, Chu CT (2013). "Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A". J Neurochem. 128 (6): 864–877. doi:10.1111/jnc.12494. PMC 3951661. PMID 24151868.
^ "Entrez Gene: PINK1 PTEN induced putative kinase 1".
^ "UniProt, Q9BXM7" (jezik: eng.). Pristupljeno 3. 12. 2021.CS1 održavanje: nepoznati jezik (link)
^ Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SH, Renton AE, Harvey RJ, Whitworth AJ, Martins LM, Abramov AY, Wood NW (2011). "PINK1 cleavage at position A103 by the mitochondrial protease PARL". Hum. Mol. Genet. 20 (5): 867–869. doi:10.1093/hmg/ddq526. PMC 3033179. PMID 21138942.
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^ Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008). "The PINK1/Parkin pathway regulates mitochondrial mitophagy". Proceedings of the National Academy of Sciences of the United States of America. 105 (5): 1638–43. doi:10.1073/pnas.0709336105. PMC 2234197. PMID 18230723.
^ Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, Millan I, Shen A, Saxton W, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B (2012). "Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria". PLOS Genetics. 8 (3): e102537. doi:10.1371/journal.pgen.1002537. PMC 3291531. PMID 22396657.
^ McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA (2014). "Parkin and PINK 1 function in a vesicular trafficking pathway regulating mitochondrial quality control". The EMBO Journal. 33 (4): 282–295. doi:10.1002/embj.201385902. PMC 3989637. PMID 24446486.
^ Pimenta de Castro I, Costa AC, Lam D, Tufi R, Fedele V, Moisoi N, Dinsdale D, Deas E, Loh SH, Martins LM (2012). "Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster". Cell Death & Differentiation. 19 (8): 1308–16. doi:10.1038/cdd.2012.5. PMC 3392634. PMID 22301916.
^ Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004). "Hereditary early-onset Parkinson's disease caused by mutations in PINK1". Science. 304 (5674): 1158–60. Bibcode:2004Sci...304.1158V. doi:10.1126/science.1096284. PMID 15087508. S2CID 33630092.
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^ ^a ^b Osgerby L, Lai YC, Thornton PJ, Amalfitano J, Le Duff CS, Jabeen I, Kadri H, Miccoli A, Tucker JH, Muqit M, Mehellou Y (2017). "Kinetin Riboside and Its ProTides Activate the Parkinson's Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization". J. Med. Chem. 60 (8): 3518–24. doi:10.1021/acs.jmedchem.6b01897. PMC 5410652. PMID 28323427.
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Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on PINK1 Type of Young-Onset Parkinson Disease

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000158828 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000028756 - Ensembl, maj 2017

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[UniProt-11] "UniProt, Q9BXM7" (jezik: eng.). Pristupljeno 3. 12. 2021.CS1 održavanje: nepoznati jezik (link)

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