| IED ID | IndEnz0002012971 |
| Enzyme Type ID | protease012971 |
| Protein Name |
E3 ubiquitin-protein ligase parkin EC 2.3.2.31 Parkin RBR E3 ubiquitin-protein ligase |
| Gene Name | Prkn Park2 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MIVFVRFNSSYGFPVEVDSDTSILQLKEVVAKRQGVPADQLRVIFAGKELPNHLTVQNCDLEQQSIVHIVQRPRRRSHETNASGGDEPQSTSEGSIWESRSLTRVDLSSHTLPVDSVGLAVILDTDSKRDSEAARGPVKPTYNSFFIYCKGPCHKVQPGKLRVQCGTCKQATLTLAQGPSCWDDVLIPNRMSGECQSPDCPGTRAEFFFKCGAHPTSDKDTSVALNLITSNRRSIPCIACTDVRSPVLVFQCNHRHVICLDCFHLYCVTRLNDRQFVHDAQLGYSLPCVAGCPNSLIKELHHFRILGEEQYTRYQQYGAEECVLQMGGVLCPRPGCGAGLLPEQGQRKVTCEGGNGLGCGFVFCRDCKEAYHEGDCDSLLEPSGATSQAYRVDKRAAEQARWEEASKETIKKTTKPCPRCNVPIEKNGGCMHMKCPQPQCKLEWCWNCGCEWNRACMGDHWFDV |
| Enzyme Length | 464 |
| Uniprot Accession Number | Q9WVS6 |
| Absorption | |
| Active Site | ACT_SITE 430; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221 |
| Activity Regulation | ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe-462 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-430, whereas the REP repressor element binds RING-1 and blocks its E2-binding site. Activation of PRKN requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-430 by the RING-0 region via an allosteric mechanism and converting PRKN to its fully-active form. According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression. {ECO:0000250|UniProtKB:O60260}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.; EC=2.3.2.31; Evidence={ECO:0000250|UniProtKB:O60260}; |
| DNA Binding | |
| EC Number | 2.3.2.31 |
| Enzyme Function | FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:32047033, PubMed:29311685). Substrates include SYT11 and VDAC1 (PubMed:32047033, PubMed:29311685). Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2 (By similarity). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:32047033, PubMed:25474007). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (By similarity). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (By similarity). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (By similarity). Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:32047033, PubMed:25474007, PubMed:22082830, PubMed:24898855). 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:32047033, PubMed:22082830, PubMed:24898855). Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin (PubMed:25474007). After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033). When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30 (PubMed:21753002). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy (By similarity). The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:24192653). This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (By similarity). Regulates motility of damaged mitochondria via 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 (By similarity). Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A (By similarity). Limits the production of reactive oxygen species (ROS) (By similarity). Regulates cyclin-E during neuronal apoptosis (By similarity). In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (By similarity). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene (By similarity). {ECO:0000250|UniProtKB:O60260, ECO:0000269|PubMed:19801972, ECO:0000269|PubMed:21753002, ECO:0000269|PubMed:22082830, ECO:0000269|PubMed:24192653, ECO:0000269|PubMed:24898855, ECO:0000269|PubMed:25474007, ECO:0000269|PubMed:29311685, ECO:0000269|PubMed:32047033}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | PATHWAY: Protein modification; protein ubiquitination. |
| nucleotide Binding | |
| Features | Active site (1); Alternative sequence (4); Beta strand (5); Chain (1); Domain (1); Helix (3); Metal binding (24); Modified residue (4); Region (6); Sequence conflict (2); Zinc finger (4) |
| Keywords | 3D-structure;Alternative splicing;Autophagy;Cell junction;Cell projection;Cytoplasm;Endoplasmic reticulum;Membrane;Metal-binding;Mitochondrion;Mitochondrion outer membrane;Nucleus;Phosphoprotein;Reference proteome;Repeat;S-nitrosylation;Synapse;Transcription;Transcription regulation;Transferase;Ubl conjugation;Ubl conjugation pathway;Zinc;Zinc-finger |
| Interact With | Q6IQX7-2; P47811; Q9ERU9; P68510; Q3U133 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000305|PubMed:10818204, ECO:0000305|PubMed:11122330}. Nucleus {ECO:0000250|UniProtKB:O60260}. Endoplasmic reticulum {ECO:0000269|PubMed:11122330}. Mitochondrion {ECO:0000269|PubMed:32047033}. Mitochondrion outer membrane {ECO:0000269|PubMed:11122330}. Cell projection, neuron projection {ECO:0000269|PubMed:11675120}. Cell junction, synapse, postsynaptic density {ECO:0000269|PubMed:11122330}. Cell junction, synapse, presynapse {ECO:0000269|PubMed:11122330}. Note=Mainly localizes in the cytosol. Co-localizes with SYT11 in neutrites. Co-localizes with SNCAIP in brainstem Lewy bodies. Translocates to dysfunctional mitochondria that have lost the mitochondrial membrane potential; recruitment to mitochondria is PINK1-dependent. Mitochondrial localization also gradually increases with cellular growth. {ECO:0000250|UniProtKB:O60260}. |
| Modified Residue | MOD_RES 65; /note=Phosphoserine; by PINK1; /evidence=ECO:0000250|UniProtKB:O60260; MOD_RES 80; /note=Phosphothreonine; /evidence=ECO:0007744|PubMed:21183079; MOD_RES 174; /note=Phosphothreonine; by PINK1; /evidence=ECO:0000250|UniProtKB:O60260; MOD_RES 216; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:O60260 |
| Post Translational Modification | PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own degradation. Also polyubiquitinated by RNF41 for proteasomal degradation. {ECO:0000250|UniProtKB:O60260}.; PTM: S-nitrosylated. {ECO:0000269|PubMed:15105460}.; PTM: Phosphorylated. Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin. Phosphorylation at Thr-174 by PINK1 and at Thr-216 is important for mitochondrial localization. {ECO:0000250|UniProtKB:O60260}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (2) |
| Cross Reference PDB | 1MG8; 2ZEQ; 3B1L; |
| Mapped Pubmed ID | 10737637; 11217851; 11978985; 12415119; 12466851; 12495618; 12628165; 12676955; 12915482; 12930822; 12972409; 14532270; 14681479; 14743368; 14985362; 15014970; 15063093; 15102676; 15249681; 15252205; 15684050; 15882845; 16092945; 16096643; 16135753; 16141072; 16150055; 16332688; 16375772; 16455660; 16517603; 16573651; 16597723; 16602821; 16698879; 16862145; 16941649; 17116640; 17336077; 17412759; 17553932; 17623040; 17883413; 17953485; 18190519; 18199761; 18295750; 18346797; 18362144; 18485927; 18574468; 18612813; 18640988; 18643794; 18671761; 18691389; 18799693; 18945890; 19057915; 19071114; 19084014; 19167501; 19229105; 19285961; 19457102; 19464273; 19546216; 19591802; 19617636; 19631192; 19680561; 19815012; 20064468; 20089134; 20089136; 20232175; 20404107; 20546895; 20573959; 20604804; 20620130; 20696900; 20810900; 20823226; 20940148; 20971077; 21113145; 21176923; 21209200; 21212098; 21267068; 21296869; 21376232; 21378096; 21454557; 21687634; 21768369; 21839811; 21858193; 21865652; 21890690; 21930938; 22008525; 22028146; 22081612; 22204976; 22215441; 22238104; 22314364; 22342752; 22342763; 22460798; 22564413; 22872702; 22954895; 22960314; 23095748; 23152496; 23256036; 23258539; 23307929; 23341467; 23359614; 23447676; 23449626; 23453807; 23588969; 23608757; 23620051; 23643664; 23737459; 23751051; 23754282; 23858059; 23917356; 23938054; 23985028; 24005326; 24075852; 24090483; 24105468; 24121678; 24187134; 24192137; 24204848; 24337465; 24379352; 24386307; 24386432; 24451648; 24516131; 24733019; 24847002; 24949970; 24952961; 24959870; 25083992; 25154397; 25216678; 25244949; 25316086; 25348719; 25349190; 25403879; 25447324; 25471590; 25486126; 25583483; 25609609; 25612572; 25654552; 25715097; 25716315; 25752611; 25779963; 25790475; 25822020; 25843045; 26024391; 26038571; 26099628; 26110811; 26159696; 26161534; 26182419; 26324925; 26387737; 26538564; 26546471; 26563499; 26746235; 26746706; 26785495; 26876175; 26921108; 26992930; 27166280; 27181353; 27206984; 27267045; 27279371; 27345367; 27430567; 27597885; 27689697; 27693468; 27754761; 27794418; 27852436; 28042097; 28063983; 28086194; 28103118; 28254618; 28336262; 28396396; 28472658; 28522833; 28695462; 28696827; 28820284; 28890682; 28938432; 28976966; 29020610; 29036556; 29040870; 29089374; 29172924; 29501495; 29561660; 29624777; 29674007; 29682760; 29692364; 29700116; 29760428; 29812989; 29893854; 29899409; 29903906; 29955050; 29981809; 29987020; 30003648; 30017357; 30063115; 30074231; 30100261; 30126943; 30135585; 30244249; 30290714; 30329047; 30378174; 30385753; 30404819; 30411223; 30449314; 30763678; 30867164; 30877201; 30908580; 30963113; 30990467; 31068772; 31089807; 31112565; 31229841; 31316206; 31339428; 31358971; 31365836; 31406131; 31409786; 31456416; 31487745; 31505254; 31619520; 31639106; 31645120; 31724300; 31727366; 31754185; 31846738; 31882005; 31889458; 31908016; 31923460; 32054064; 32080200; 32291905; 32364493; 32427312; 32427925; 32444656; 32457148; 32499407; 32545383; 32597196; 32627655; 32653576; 32718208; 32824240; 32936696; 32976921; 33020660; 33037272; 33126429; 33137712; 33155636; 33164878; 33218272; 33571581; 33636335; 33851544; 34450375; 34655600; 9560156; |
| Motif | |
| Gene Encoded By | |
| Mass | 51,618 |
| Kinetics | |
| Metal Binding | METAL 237; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 240; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 252; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 256; /note=Zinc 2; via pros nitrogen; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 259; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 262; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 288; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 292; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 331; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 336; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 351; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 359; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 364; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 367; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 372; /note=Zinc 4; via tele nitrogen; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 376; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 417; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 420; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 435; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 440; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 445; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 448; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 456; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221; METAL 460; /note=Zinc 6; via tele nitrogen; /evidence=ECO:0000255|PROSITE-ProRule:PRU01221 |
| Rhea ID | |
| Cross Reference Brenda |