Prkn
entrez
56816
canonical
uniprot
Q9JK66
canonical
ensembl
ENSRNOG00000055547
resolver
ensp
ENSRNOP00000070559
resolver
ensp
ENSRNOP00000075137
resolver
ensp
ENSRNOP00000077507
resolver
enst
ENSRNOT00000089439
resolver
genesymbol
Prkn
resolver
genesymbol_syn
AABR07001519.1
resolver
genesymbol_syn
Park2
resolver
uniprot
A0A0G2JY87
resolver
uniprot
D3JVU6
resolver
uniprot
Q8K5C3
resolver
uniprot
Q8K5C4
resolver
uniprot
Q8K5C5
resolver
uniprot
Q8K5C6
resolver
uniprot
Q8VHY6
resolver
uniprot
Q9JLL1
resolver
uniprot
Q9JM64
resolver
uniprot_entry
A0A0G2JY87_RAT
resolver
uniprot_entry
D3JVU6_RAT
resolver
uniprot_entry
PRKN_RAT
resolver
uniprot_sec
Q8K5C3
resolver
uniprot_sec
Q8K5C4
resolver
uniprot_sec
Q8K5C5
resolver
uniprot_sec
Q8K5C6
resolver
uniprot_sec
Q8VHY6
resolver
uniprot_sec
Q9JLL1
resolver
uniprot_sec
Q9JM64
resolver
activity_regulation
ACTIVITY REGULATION: In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, 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-431 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. In addition, ISG15 conjugation positively regulates its ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation. {ECO:0000250|UniProtKB:O60260, ECO:0000269|PubMed:23661642}.
uniprot
proteins
amino_acid_sequence
MIVFVRFNSSYGFPVEVDSDTSIFQLKEVVAKRQGVPADQLRVIFAGKELQNHLTVQNCDLEQQSIVHIVQRPQRKSHETNASGGDKPQSTPEGSIWEPRSLTRVDLSSHILPADSVGLAVILDTDSKSDSEAARGPEAKPTYHSFFVYCKGPCHKVQPGKLRVQCGTCRQATLTLAQGPSCWDDVLIPNRMSGECQSPDCPGTRAEFFFKCGAHPTSDKDTSVALNLITNNSRSIPCIACTDVRNPVLVFQCNHRHVICLDCFHLYCVTRLNDRQFVHDAQLGYSLPCVAGCPNSLIKELHHFRILGEEQYNRYQQYGAEECVLQMGGVLCPRPGCGAGLLPEQGQKKVTCEGGNGLGCGFVFCRDCKEAYHEGECDSMFEASGATSQAYRVDQRAAEQARWEEASKETIKKTTKPCPRCNVPIEKNGGCMHMKCPQPQCKLEWCWNCGCEWNRACMGDHWFDV
uniprot
proteins
ec_number
2.3.2.31
uniprot
proteins
function
FUNCTION: Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. 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. Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. 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. 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. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. 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. 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. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. 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. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. 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. 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. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene. {ECO:0000250|UniProtKB:O60260}.
uniprot
proteins
mass_dalton
51709
uniprot
proteins
mutagenesis
MUTAGEN 403; /note="W->A: Increased autoubiquitination."; /evidence="ECO:0000269|PubMed:23661642
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination.
uniprot
proteins
post_translational_modification
PTM: Auto-ubiquitinates in an E2-dependent manner leading to its own degradation (PubMed:23661642). Also polyubiquitinated by RNF41 for proteasomal degradation (By similarity). {ECO:0000250|UniProtKB:O60260, ECO:0000269|PubMed:23661642}.; PTM: S-nitrosylated. {ECO:0000250|UniProtKB:O60260}.; PTM: Phosphorylated. Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin. Phosphorylation at Thr-175 by PINK1 and at Thr-217 is important for mitochondrial localization. {ECO:0000250|UniProtKB:O60260}.
uniprot
proteins
protein_family
Parkin subfamily
uniprot
proteins
protein_family
RBR family
uniprot
proteins
pubmed
10686358
uniprot
proteins
pubmed
10737637
uniprot
proteins
pubmed
12925569
uniprot
proteins
pubmed
16955485
uniprot
proteins
pubmed
23661642
uniprot
proteins
sequence_length
465
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:12925569}. Nucleus {ECO:0000250|UniProtKB:O60260}. Endoplasmic reticulum {ECO:0000250|UniProtKB:O60260}. Mitochondrion {ECO:0000250|UniProtKB:O60260}. Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q9WVS6}. Cell projection, neuron projection {ECO:0000269|PubMed:12925569}. Postsynaptic density {ECO:0000250|UniProtKB:Q9WVS6}. Presynapse {ECO:0000250|UniProtKB:Q9WVS6}. 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}.
uniprot
proteins