| IED ID | IndEnz0002011834 |
| Enzyme Type ID | protease011834 |
| Protein Name |
Serine/threonine-protein kinase Pink1, mitochondrial EC 2.7.11.1 PTEN-induced putative kinase 1 |
| Gene Name | Pink1 CG4523 |
| Organism | Drosophila melanogaster (Fruit fly) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Protostomia Ecdysozoa Panarthropoda Arthropoda Mandibulata Pancrustacea Hexapoda Insecta Dicondylia Pterygota (winged insects) Neoptera Endopterygota Diptera Brachycera Muscomorpha Eremoneura Cyclorrhapha Schizophora Acalyptratae Ephydroidea Drosophilidae (pomace flies) Drosophilinae Drosophilini Drosophila (fruit flies) Sophophora melanogaster group melanogaster subgroup Drosophila melanogaster (Fruit fly) |
| Enzyme Sequence | MSVRLLTVRLIKHGRYILRSYCKRDIHANILDQNQLKTRSKRGFPLPSTAANVLRTTPQQAAKSVVNVVPRTINSPSGSPFNGSGSSPTSSSGIFRVGQHARKLFIDNILSRVTTTYSEDLRQRATRKLFFGDSAPFFALIGVSLASGSGVLSKEDELEGVCWEIREAASRLQNAWNHDEISDTLDSKFTIDDLEIGPPIAKGCAAVVYAADFKKDVASDGASLHTDAQPQATPAFAPNSWSTHEMMSPLQNMSRFVHNFGGSVDNVFHYSQPSAASDFVGAQSREQDQRHHEQQQHQNQEQEQHQNQEPSSSAFNVTSPANSNINSSVDSYPLALKMMFNYDIQSNALSILRAMYKETVPARQRGMNEAADEWERLLQNQTVHLPRHPNIVCMFGFFCDEVRNFPDGHLLYPVAQPQRINPQGYGRNMSLYLLMKRYDHSLRGLLDSQDLSTRNRILLLAQMLEAVNHLSRHGVAHRDLKSDNVLIELQDDAAPVLVLSDFGCCLADKVHGLRLPYVSHDVDKGGNAALMAPEIFNTMPGPFAVLNYGKADLWACGALAYEIFGNRNPFYSSSGGMARERGEMTLSLRNSDYRQDQLPPMSDACPPLLQQLVYNILNPNPSKRVSPDIAANVVQLFLWAPSNWLKAGGMPNSPEILQWLLSLTTKIMCEGRPQMGAGLMPVASCGNRRAYVEYLLICSFLARARLRRIRGALNWIQNVVA |
| Enzyme Length | 721 |
| Uniprot Accession Number | Q0KHV6 |
| Absorption | |
| Active Site | ACT_SITE 479; /note=Proton acceptor; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Activity Regulation | |
| Binding Site | BINDING 337; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:27906179}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:27906179}; |
| DNA Binding | |
| EC Number | 2.7.11.1 |
| Enzyme Function | FUNCTION: Acts as a serine/threonine-protein kinase (PubMed:16672980, PubMed:18799731, PubMed:16672981, PubMed:16818890, PubMed:16938835, PubMed:18230723, PubMed:18443288, PubMed:18957282, PubMed:20194754, PubMed:22645651, PubMed:24901221, PubMed:25474007, PubMed:32484300). Exhibits a substrate preference for proline at position P+1 and a general preference at several residues for basic residues such as arginine (By similarity). Also exhibits moderate preferences for a phosphotyrosine at position P-3 and a tryptophan at P-5 (By similarity). Protects against mitochondrial dysfunction during cellular stress by phosphorylating mitochondrial proteins such as park and likely Drp1, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:16672980, PubMed:18799731, PubMed:16672981, PubMed:16818890, PubMed:16938835, PubMed:18230723, PubMed:18443288, PubMed:18957282, PubMed:20194754, PubMed:22645651, PubMed:24901221, PubMed:25474007, PubMed:32484300). Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:16672980, PubMed:16672981, PubMed:16818890, PubMed:16938835, PubMed:18230723, PubMed:18443288, PubMed:18799731, PubMed:18957282, PubMed:20194754, PubMed:23509287, PubMed:24901221, PubMed:25474007). Appears to be particularly important in maintaining the physiology and function of cells with high energy demands that are undergoing stress or altered metabolic environment, including spermatids, muscle cells and neurons such as the dopaminergic (DA) neurons (PubMed:16672980, PubMed:16672981, PubMed:16818890, PubMed:16938835, PubMed:18443288, PubMed:18799731, PubMed:22396657, PubMed:24901221, PubMed:28435104, PubMed:32138754). Mediates the translocation and activation of park at the outer membrane (OMM) of dysfunctional/depolarized mitochondria (PubMed:24901221, PubMed:20194754, PubMed:18957282, PubMed:18799731, PubMed:25474007, PubMed:27906179). At the OMM of damaged mitochondria, phosphorylates pre-existing polyubiquitin chains, the Pink1-phosphorylated polyubiquitin then recruits park from the cytosol to the OMM where park is fully activated by phosphorylation at 'Ser-94' by Pink1 (PubMed:24901221, PubMed:20194754, PubMed:18957282, PubMed:18799731, PubMed:25474007, PubMed:27906179). When cellular stress results in irreversible mitochondrial damage, functions with park to promote the clearance of dysfunctional and/or depolarized mitochondria by selective autophagy (mitophagy) (PubMed:16672980, PubMed:16672981, PubMed:20194754, PubMed:18957282, PubMed:23509287, PubMed:25474007). The Pink1-park pathway also promotes fission and/or inhibits fusion of damaged mitochondria, by phosphorylating and thus promoting the park-dependent degradation of proteins involved in mitochondrial fusion/fission such as Marf, Opa1 and fzo (PubMed:18443288, PubMed:18799731, PubMed:18230723, PubMed:20194754, PubMed:24901221). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:18799731, PubMed:18230723, PubMed:20194754, PubMed:24901221). Also likely to promote mitochondrial fission independently of park and Atg7-mediated mitophagy, via the phosphorylation and activation of Drp1 (PubMed:18443288, PubMed:32484300). Regulates motility of damaged mitochondria by phosphorylating Miro which likely promotes its park-dependent degradation by the proteasome; in motor neurons, this inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria being eliminated in the soma (PubMed:22396657). The Pink1-park pathway is also involved in mitochondrial regeneration processes such as promoting mitochondrial biogenesis, activating localized mitochondrial repair, promoting selective turnover of mitochondrial proteins and initiating the mitochondrial import of endogenous proteins (PubMed:16672980, PubMed:23509287, PubMed:30772175). Involved in mitochondrial biogenesis by promoting the park-dependent ubiquitination of transcriptional repressor Paris which leads to its subsequent proteasomal degradation and allows activation of the transcription factor srl (PubMed:32138754). Functions with park to promote localized mitochondrial repair by activating the translation of specific nuclear-encoded mitochondrial RNAs (nc-mtRNAs) on the mitochondrial surface, including several key electron transport chain component nc-mtRNAs (PubMed:23509287). During oogenesis, phosphorylates and inactivates larp on the membrane of defective mitochondria, thus impairing local translation and mtDNA replication and consequently, reducing transmission of deleterious mtDNA mutations to the mature oocyte (PubMed:30772175). {ECO:0000250|UniProtKB:D6WMX4, ECO:0000269|PubMed:16672980, ECO:0000269|PubMed:16672981, ECO:0000269|PubMed:16818890, ECO:0000269|PubMed:16938835, ECO:0000269|PubMed:18230723, ECO:0000269|PubMed:18443288, ECO:0000269|PubMed:18799731, ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:20194754, ECO:0000269|PubMed:22396657, ECO:0000269|PubMed:22645651, ECO:0000269|PubMed:23509287, ECO:0000269|PubMed:24901221, ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:27906179, ECO:0000269|PubMed:28435104, ECO:0000269|PubMed:30772175, ECO:0000269|PubMed:32138754, ECO:0000269|PubMed:32484300}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 310..318; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Binding site (1); Chain (1); Compositional bias (2); Domain (1); Metal binding (4); Modified residue (1); Mutagenesis (6); Nucleotide binding (1); Region (1); Sequence conflict (1); Topological domain (2); Transit peptide (1); Transmembrane (1) |
| Keywords | ATP-binding;Autophagy;Cytoplasm;Kinase;Magnesium;Membrane;Metal-binding;Mitochondrion;Mitochondrion inner membrane;Mitochondrion outer membrane;Nucleotide-binding;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Transferase;Transit peptide;Transmembrane;Transmembrane helix |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:30772175, ECO:0000305|PubMed:16672980, ECO:0000305|PubMed:16672981, ECO:0000305|PubMed:19048081}; Single-pass membrane protein {ECO:0000255}. Mitochondrion inner membrane {ECO:0000305|PubMed:16672980, ECO:0000305|PubMed:16672981, ECO:0000305|PubMed:19048081}; Single-pass membrane protein {ECO:0000255}. Cytoplasm, cytosol {ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19048081}. Note=Localizes mostly in mitochondrion, and the smaller proteolytic processed fragment localizes in the cytosol as well (PubMed:19048081). When mitochondria are damaged, defective and/or enriched with deleterious mtDNA mutations, Pink1 import is arrested which induces its accumulation on the outer mitochondrial membrane where it acquires kinase activity (PubMed:18957282, PubMed:30772175). Detected in nebenkerns (PubMed:16672981). {ECO:0000269|PubMed:16672981, ECO:0000269|PubMed:18957282, ECO:0000269|PubMed:19048081, ECO:0000269|PubMed:30772175}. |
| Modified Residue | MOD_RES 346; /note="Phosphoserine; by autocatalysis"; /evidence="ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:27906179" |
| Post Translational Modification | PTM: Proteolytically cleaved (PubMed:19048081). In healthy cells, the precursor is continuously imported into mitochondria where it is proteolytically cleaved into its short form by the mitochondrial rhomboid protease rho-7 (PubMed:19048081). The short form is then released into the cytosol where it rapidly undergoes proteasome-dependent degradation (Probable). 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:27906179). {ECO:0000269|PubMed:19048081, ECO:0000269|PubMed:27906179, ECO:0000305|PubMed:19048081}.; PTM: Autophosphorylated on Ser-346, which activates kinase activity (PubMed:25474007, PubMed:27906179). Loss of mitochondrial membrane potential results in the precursor accumulating on the outer mitochondrial membrane (OMM) where it is activated by autophosphorylation at Ser-346 (PubMed:27906179). Autophosphorylation is sufficient and essential for selective recruitment of park to depolarized mitochondria, likely via Pink1-dependent phosphorylation of polyubiquitin chains (PubMed:25474007, PubMed:27906179). {ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:27906179}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 11529271; 14605208; 15630418; 16762338; 16810237; 16839867; 16938856; 16998822; 17051205; 17418114; 17498648; 18084299; 18690062; 19056353; 19088817; 19118185; 19282869; 19378456; 19546216; 19684592; 19692353; 19786080; 20049710; 20220848; 20351285; 20371351; 20383334; 20457924; 20817094; 20950655; 21074052; 21151574; 21151955; 21274005; 21447707; 21504582; 21512585; 21768365; 21856777; 21976688; 22078885; 22219196; 22242018; 22301916; 22347370; 22378780; 22388932; 22486164; 22567011; 22582012; 22610403; 22649226; 22653599; 22691499; 22940086; 22952763; 23024178; 23071443; 23077619; 23087837; 23303188; 23328674; 23348839; 23498974; 23523076; 23525905; 23544124; 23637640; 23867819; 23933751; 24009736; 24028575; 24099009; 24157867; 24192653; 24198346; 24243023; 24244323; 24352421; 24441527; 24473149; 24652937; 24790636; 24862573; 24874806; 24896179; 24898855; 24912190; 24949430; 24965893; 24965943; 25040725; 25062361; 25091506; 25145627; 25284370; 25294943; 25312911; 25336644; 25340511; 25376463; 25389385; 25412178; 25557247; 25565208; 25594180; 25611391; 25612572; 25708988; 25743185; 25761903; 25849929; 25960916; 26035866; 26109662; 26151724; 26210484; 26214738; 26251041; 26413413; 26550693; 26597171; 26599788; 26611999; 26631731; 26896675; 26931463; 27054334; 27076081; 27251035; 27336715; 27451905; 27454757; 27502471; 27528605; 27575041; 27716788; 27794540; 27841259; 27904993; 28011627; 28106473; 28178568; 28211869; 28211874; 28286087; 28322724; 28541509; 28589937; 28596378; 28663346; 28716706; 28737703; 28778978; 28782874; 28827794; 28848400; 28945745; 29142100; 29355849; 29361562; 29411967; 29456190; 29500189; 29563254; 29563863; 29686647; 29809156; 29861391; 29887339; 29909722; 29951814; 30001323; 30027908; 30185553; 30219582; 30237395; 30248358; 30249595; 30295680; 30339961; 30354903; 30376466; 30379317; 30393142; 30526176; 30545438; 30741974; 30988163; 30991634; 31068592; 31080045; 31092924; 31101394; 31120803; 31132524; 31160709; 31291788; 31320986; 31378462; 31434710; 31524631; 31548400; 31555733; 31562951; 31564441; 31646538; 31714929; 31722958; 31740269; 31907391; 31936094; 32035987; 32060339; 32157731; 32200800; 32200806; 32252301; 32323790; 32335362; 32357532; 32386191; 32475477; 32537848; 32544407; 32567155; 32620249; 32629421; 32749068; 32766952; 32873392; 32898622; 32937783; 32941465; 32958650; 33064773; 33085661; 33111208; 33113344; 33170836; 33363053; 33378446; 33761355; 33772006; 33800736; 33852843; 33857132; 33966044; 34002678; 34012959; 34043205; 34074800; 34218254; 34232246; 34244144; 34322715; 34404758; 34421573; 34506510; 34550070; |
| Motif | |
| Gene Encoded By | |
| Mass | 80,228 |
| Kinetics | |
| Metal Binding | METAL 358; /note=Magnesium 1; /evidence=ECO:0000250|UniProtKB:D6WMX4; METAL 484; /note=Magnesium 2; /evidence=ECO:0000250|UniProtKB:D6WMX4; METAL 501; /note=Magnesium 1; /evidence=ECO:0000250|UniProtKB:D6WMX4; METAL 501; /note=Magnesium 2; /evidence=ECO:0000250|UniProtKB:D6WMX4 |
| Rhea ID | RHEA:17989; RHEA:46608 |
| Cross Reference Brenda |