PINK1
entrez
65018
canonical
uniprot
Q9BXM7
canonical
ensembl
ENSG00000158828
resolver
ensp
ENSP00000364204
resolver
genesymbol
PINK1
resolver
hgnc
HGNC:14581
resolver
uniprot
Q8N6T9
resolver
uniprot
Q8NBU3
resolver
uniprot
Q96DE4
resolver
uniprot_entry
PINK1_HUMAN
resolver
uniprot_sec
Q8N6T9
resolver
uniprot_sec
Q8NBU3
resolver
uniprot_sec
Q96DE4
resolver
amino_acid_sequence
MAVRQALGRGLQLGRALLLRFTGKPGRAYGLGRPGPAAGCVRGERPGWAAGPGAEPRRVGLGLPNRLRFFRQSVAGLAARLQRQFVVRAWGCAGPCGRAVFLAFGLGLGLIEEKQAESRRAVSACQEIQAIFTQKSKPGPDPLDTRRLQGFRLEEYLIGQSIGKGCSAAVYEATMPTLPQNLEVTKSTGLLPGRGPGTSAPGEGQERAPGAPAFPLAIKMMWNISAGSSSEAILNTMSQELVPASRVALAGEYGAVTYRKSKRGPKQLAPHPNIIRVLRAFTSSVPLLPGALVDYPDVLPSRLHPEGLGHGRTLFLVMKNYPCTLRQYLCVNTPSPRLAAMMLLQLLEGVDHLVQQGIAHRDLKSDNILVELDPDGCPWLVIADFGCCLADESIGLQLPFSSWYVDRGGNGCLMAPEVSTARPGPRAVIDYSKADAWAVGAIAYEIFGLVNPFYGQGKAHLESRSYQEAQLPALPESVPPDVRQLVRALLQREASKRPSARVAANVLHLSLWGEHILALKNLKLDKMVGWLLQQSAATLLANRLTEKCCVETKMKMLFLANLECETLCQAALLLCSWRAAL
uniprot
proteins
disease_involvement
DISEASE: Parkinson disease 6 (PARK6) [MIM:605909]: An early-onset form of Parkinson disease, a neurodegenerative disorder characterized by parkinsonian signs such as rigidity, resting tremor and bradykinesia. A subset of patients manifest additional symptoms including hyperreflexia, autonomic instability, dementia and psychiatric disturbances. Symptoms show diurnal fluctuation and can improve after sleep. PARK6 pathogenesis involves respiratory complex I deficiency causing mitochondrial depolarization and dysfunction. Inheritance is autosomal recessive. {ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:15349860, ECO:0000269|PubMed:15349870, ECO:0000269|PubMed:15505171, ECO:0000269|PubMed:15596610, ECO:0000269|PubMed:15955953, ECO:0000269|PubMed:15970950, ECO:0000269|PubMed:16009891, ECO:0000269|PubMed:16207217, ECO:0000269|PubMed:16207731, ECO:0000269|PubMed:16257123, ECO:0000269|PubMed:16401616, ECO:0000269|PubMed:16482571, ECO:0000269|PubMed:16632486, ECO:0000269|PubMed:16966503, ECO:0000269|PubMed:17030667, ECO:0000269|PubMed:18286320, ECO:0000269|PubMed:18785233, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19351622, ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22043288, ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22956510, ECO:0000269|PubMed:24652937, ECO:0000269|PubMed:24784582}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
function
FUNCTION: Serine/threonine-protein kinase which acts as a sensor of mitochondrial damage and protects against mitochondrial dysfunction during cellular stress (PubMed:40080546). It phosphorylates mitochondrial proteins to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:14607334, PubMed:15087508, PubMed:18443288, PubMed:18957282, PubMed:19229105, PubMed:19966284, PubMed:20404107, PubMed:20547144, PubMed:20798600, PubMed:22396657, PubMed:23620051, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:24896179, PubMed:24898855, PubMed:25527291, PubMed:32484300). In healthy mitochondria, PINK1 is translocated across the mitochondrial outer membrane (MOM) via the translocase of the outer membrane (TOM) complex, and inserted into the mitochondrial inner membrane (MIM) via the translocase of the inner membrane (TIM23) complex where it is cleaved and released into the cytosol (PubMed:40080546). Depending on the severity of mitochondrial damage, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to eliminating severely damaged mitochondria via PINK1-PRKN-dependent mitophagy (PubMed:14607334, PubMed:15087508, PubMed:18443288, PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:22396657, PubMed:23620051, PubMed:23933751, PubMed:24898855, PubMed:32047033, PubMed:32484300). When cellular stress results in irreversible mitochondrial damage, PINK1 accumulates at the outer mitochondrial membrane (OMM) where it phosphorylates pre-existing polyubiquitin chains at 'Ser-65', recruits PRKN from the cytosol to the OMM and activates PRKN by phosphorylation at 'Ser-65'; activated PRKN then ubiquitinates VDAC1 and other OMM proteins to initiate mitophagy (PubMed:14607334, PubMed:15087508, PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291, PubMed:32047033, PubMed:40080546). The PINK1-PRKN pathway also promotes fission of damaged mitochondria through phosphorylation and PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051). Also promotes mitochondrial fission independently of PRKN and ATG7-mediated mitophagy, via the phosphorylation and activation of DNM1L (PubMed:18443288, PubMed:32484300). Regulates motility of damaged mitochondria by promoting the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657). Required for ubiquinone reduction by mitochondrial complex I by mediating phosphorylation of complex I subunit NDUFA10 (By similarity). Phosphorylates LETM1, positively regulating its mitochondrial calcium transport activity (PubMed:29123128). {ECO:0000250|UniProtKB:Q99MQ3, ECO:0000269|PubMed:14607334, ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:18443288, ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:19966284, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:20547144, ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:23754282, ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:24660806, ECO:0000269|PubMed:24751536, ECO:0000269|PubMed:24784582, ECO:0000269|PubMed:24896179, ECO:0000269|PubMed:24898855, ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:25527291, ECO:0000269|PubMed:29123128, ECO:0000269|PubMed:32047033, ECO:0000269|PubMed:32484300, ECO:0000269|PubMed:40080546}.
uniprot
proteins
mass_dalton
62769
uniprot
proteins
mutagenesis
MUTAGEN 112..117; /note="EEKQAE->AAKQAA: In 3EA; impaired ability to localize to the outer mitochondrial membrane."; /evidence="ECO:0000269|PubMed:30733118"; MUTAGEN 131; /note="I->E: Under depolarizing conditions, it results in loss of interaction with TOMM20 and fails to support PINK1-TOM-TIM23 complex assembly and mitophagy activation."; /evidence="ECO:0000269|PubMed:38416681"; MUTAGEN 219; /note="K->A: Abolishes MFN2 phosphorylation and interaction with PRKN; when associated with Ala-362 and Ala-384."; /evidence="ECO:0000269|PubMed:23620051"; MUTAGEN 219; /note="K->M: Loss of enzyme activity and impaired localization of PRKN to mitochondria; when associated with A-362 and A-384."; /evidence="ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:32047033"; MUTAGEN 362; /note="D->A: Abolishes MFN2 phosphorylation and interaction with PRKN; when associated with A-219 and A-384. Loss of enzyme activity and impaired localization of PRKN to mitochondria; when associated with M-219 and A-384."; /evidence="ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033"; MUTAGEN 384; /note="D->A: Abolishes MFN2 phosphorylation and interaction with PRKN; when associated with A-219 and A-362. Loss of enzyme activity and impaired localization of PRKN to mitochondria; when associated with M-219 and A-362."; /evidence="ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:23620051, ECO:0000269|PubMed:32047033"; MUTAGEN 384; /note="D->N: Loss of activity. Abolishes Drp1 phosphorylation. No effect on localization to mitochondria."; /evidence="ECO:0000269|PubMed:32484300"; MUTAGEN 532; /note="L->A: Under depolarizing conditions, it results in severely reduced autophosphorylation on S-228 and loss of kinase activation."; /evidence="ECO:0000269|PubMed:38848361"; MUTAGEN 536; /note="A->E: Under depolarizing conditions, it results in loss of interaction with TOMM20 and fails to support PINK1-TOM-TIM23 complex assembly and mitophagy activation."; /evidence="ECO:0000269|PubMed:38416681"; MUTAGEN 536; /note="A->S: Under depolarizing conditions, it fails to support PINK1-TOM-TIM23 complex assembly and mitophagy activation."; /evidence="ECO:0000269|PubMed:38416681"; MUTAGEN 539; /note="L->A: Under depolarizing conditions, it results in severely reduced autophosphorylation on S-228 and loss of kinase activation."; /evidence="ECO:0000269|PubMed:38848361"; MUTAGEN 540; /note="L->A: Under depolarizing conditions, does not affect autophosphorylation on S-228 and kinase activation."; /evidence="ECO:0000269|PubMed:38848361"; MUTAGEN 540; /note="L->K: Under depolarizing conditions, it results in loss of interaction with TOMM20 and fails to support PINK1-TOM-TIM23 complex assembly and mitophagy activation."; /evidence="ECO:0000269|PubMed:38416681"; MUTAGEN 543; /note="R->D: No effect on interaction with TOMM20 and mitophagy activation under depolarizing conditions."; /evidence="ECO:0000269|PubMed:38416681"; MUTAGEN 543; /note="R->G: Under depolarizing conditions, it fails to support PINK1-TOM-TIM23 complex assembly and mitophagy activation."; /evidence="ECO:0000269|PubMed:38416681
uniprot
proteins
post_translational_modification
PTM: Proteolytically cleaved (PubMed:19229105, PubMed:22354088, PubMed:30733118). In healthy cells, the precursor is continuously imported into the inner mitochondrial membrane (IMM), where it is proteolytically cleaved by mitochondrial-processing peptidase (MPP) and then undergoes further proteolytic cleavage by PARL or AFG3L2 to give rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088). The 52 kDa short form is then released into the cytosol where it rapidly undergoes proteasome-dependent degradation (PubMed:20404107). In unhealthy cells, when cellular stress conditions lead to the loss of mitochondrial membrane potential, mitochondrial import is impaired leading to the precursor accumulating on the outer mitochondrial membrane (OMM) (PubMed:20404107, PubMed:30733118). If accumulation at the OMM fails and it is imported into the depolarized mitochondria, it undergoes cleavage by the IMM protease OMA1, promoting its subsequent degradation by the proteasome (PubMed:30733118). {ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:22354088, ECO:0000269|PubMed:30733118}.; PTM: Autophosphorylated (PubMed:18957282, PubMed:20404107, PubMed:22910362). Loss of mitochondrial membrane potential results in the precursor accumulating on the outer mitochondrial membrane (OMM) where it is activated by autophosphorylation (PubMed:18957282, PubMed:20404107, PubMed:22910362). Autophosphorylation at Ser-228 and Ser-402 is sufficient and essential for selective recruitment of PRKN to depolarized mitochondria, via PINK1-dependent phosphorylation of ubiquitin and maybe PRKN (PubMed:18957282, PubMed:22910362). {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20404107, ECO:0000269|PubMed:22910362}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
Ser/Thr protein kinase family
uniprot
proteins
pubmed
11494141
uniprot
proteins
pubmed
14607334
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15087508
uniprot
proteins
pubmed
15349860
uniprot
proteins
pubmed
15349870
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15505171
uniprot
proteins
pubmed
15596610
uniprot
proteins
pubmed
15955953
uniprot
proteins
pubmed
15970950
uniprot
proteins
pubmed
16009891
uniprot
proteins
pubmed
16207217
uniprot
proteins
pubmed
16207731
uniprot
proteins
pubmed
16257123
uniprot
proteins
pubmed
16401616
uniprot
proteins
pubmed
16482571
uniprot
proteins
pubmed
16632486
uniprot
proteins
pubmed
16672980
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
16966503
uniprot
proteins
pubmed
16969854
uniprot
proteins
pubmed
17030667
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
18286320
uniprot
proteins
pubmed
18330912
uniprot
proteins
pubmed
18443288
uniprot
proteins
pubmed
18687899
uniprot
proteins
pubmed
18785233
uniprot
proteins
pubmed
18957282
uniprot
proteins
pubmed
19229105
uniprot
proteins
pubmed
19351622
uniprot
proteins
pubmed
19966284
uniprot
proteins
pubmed
20404107
uniprot
proteins
pubmed
20547144
uniprot
proteins
pubmed
20798600
uniprot
proteins
pubmed
22043288
uniprot
proteins
pubmed
22354088
uniprot
proteins
pubmed
22396657
uniprot
proteins
pubmed
22910362
uniprot
proteins
pubmed
22956510
uniprot
proteins
pubmed
23620051
uniprot
proteins
pubmed
23754282
uniprot
proteins
pubmed
23933751
uniprot
proteins
pubmed
24652937
uniprot
proteins
pubmed
24660806
uniprot
proteins
pubmed
24751536
uniprot
proteins
pubmed
24784582
uniprot
proteins
pubmed
24896179
uniprot
proteins
pubmed
24898855
uniprot
proteins
pubmed
25474007
uniprot
proteins
pubmed
25527291
uniprot
proteins
pubmed
29123128
uniprot
proteins
pubmed
30733118
uniprot
proteins
pubmed
31536960
uniprot
proteins
pubmed
32047033
uniprot
proteins
pubmed
32484300
uniprot
proteins
pubmed
35391620
uniprot
proteins
pubmed
37160114
uniprot
proteins
pubmed
38416681
uniprot
proteins
pubmed
38848361
uniprot
proteins
pubmed
40080546
uniprot
proteins
sequence_length
581
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000269|PubMed:15087508, ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:18687899, ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:23933751, ECO:0000269|PubMed:31536960}. Mitochondrion inner membrane {ECO:0000250|UniProtKB:Q99MQ3}. Cytoplasm, cytosol {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:20798600, ECO:0000269|PubMed:22354088}. Note=Localizes mostly in mitochondrion and the two smaller proteolytic processed fragments localize mainly in cytosol (PubMed:19229105). In healthy mitochondria, PINK1 is translocated across the mitochondrial membranes (PubMed:40080546). Upon mitochondrial membrane depolarization following damage, PINK1 import is stalled, which induces its accumulation in the outer mitochondrial membrane and the activation of its kinase activity (PubMed:18957282, PubMed:40080546). {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19229105, ECO:0000269|PubMed:40080546}.
uniprot
proteins