Q7KTX7
SS
Gene name |
park (parkin, CG10523) |
Protein name |
E3 ubiquitin-protein ligase parkin |
Names |
EC 2.3.2.31 |
Species |
Drosophila melanogaster (Fruit fly) |
KEGG Pathway |
dme:Dmel_CG10523 |
EC number |
2.3.2.31: Aminoacyltransferases |
Protein Class |
|
Descriptions
Parkin belongs to the RBR subfamily of E3 ubiquitin ligases that function by transferring Ub from an E2-conjugating enzyme to a substrate through an E3-Ub intermediate. Parkin contains an N-terminal ubiquitin-like (UbL) domain connected through a linker to four zinc-coordinating domains consisting of RING0, following by the RBR (RING1, In-Between-RING (IBR), RING2) module common to other E3 Ub ligases. RING1 contains an E2 binding site and RING2 contains a catalytic cysteine that is an acceptor for an ubiquitin from RING1-bound E2~Ub forming an intermediate (E3~Ub) that leads to substrate or autoubiquitination.<br>Structural studies revealed that Parkin, in its basal state, adopts an autoinhibited conformation with several distinct sites of inhibition. First, the UbL domain is bound to RING1 such that Ser65 is poorly accessible for phosphorylation by PINK1. Second, the Repressor Element of Parkin (REP) blocks the site of E2 Ub-conjugating enzyme binding on RING1. Finally, the RING0 domain binds to RING2, where it occludes the Cys431 Ub acceptor site. PINK1 stimulates parkin activity through phosphorylation of both Ub and parkin's UbL domain at an equivalent serine 65 position in sequence and structure. The phosphorylation of both the UbL domain and Ub are required to activate parkin by releasing the UbL domain, forming an extended structure needed to facilitate E2-Ub binding.
Autoinhibitory domains (AIDs)
Target domain |
249-339 (RING1 domain) |
Relief mechanism |
PTM |
Assay |
|
Accessory elements
No accessory elements
References
- Byrd RA et al. (2013) "Compact Parkin only: insights into the structure of an autoinhibited ubiquitin ligase", The EMBO journal, 32, 2087-9
- Aguirre JD et al. (2017) "Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation", Proceedings of the National Academy of Sciences of the United States of America, 114, 298-303
- Kumar A et al. (2015) "Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis", The EMBO journal, 34, 2506-21
- Tang MY et al. (2017) "Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation", Nature communications, 8, 14697
- Seirafi M et al. (2015) "Parkin structure and function", The FEBS journal, 282, 2076-88
- Gladkova C et al. (2018) "Mechanism of parkin activation by PINK1", Nature, 559, 410-414
- Tomoo K et al. (2008) "Crystal structure and molecular dynamics simulation of ubiquitin-like domain of murine parkin", Biochimica et biophysica acta, 1784, 1059-67
Autoinhibited structure
Activated structure
3 structures for Q7KTX7
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| 2LWR | NMR | - | A | 417-482 | PDB |
| 2M48 | NMR | - | A | 342-482 | PDB |
| AF-Q7KTX7-F1 | Predicted | AlphaFoldDB |
No variants for Q7KTX7
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| No variants for Q7KTX7 | |||||
No associated diseases with Q7KTX7
9 regional properties for Q7KTX7
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Ubiquitin-like domain | 30 - 101 | IPR000626 |
| domain | IBR domain | 334 - 394 | IPR002867-1 |
| domain | IBR domain | 419 - 475 | IPR002867-2 |
| domain | RING/Ubox-like zinc-binding domain | 249 - 339 | IPR041170 |
| domain | Parkin, RING/Ubox like zinc-binding domain | 158 - 236 | IPR041565 |
| domain | TRIAD supradomain | 255 - 482 | IPR044066 |
| domain | E3 ubiquitin-protein ligase parkin, BRcat domain | 322 - 398 | IPR047534 |
| domain | E3 ubiquitin-protein ligase parkin, RING finger, HC subclass | 257 - 315 | IPR047535 |
| domain | E3 ubiquitin-protein ligase parkin, Rcat domain | 428 - 481 | IPR047536 |
Functions
| Description | ||
|---|---|---|
| EC Number | 2.3.2.31 | Aminoacyltransferases |
| Subcellular Localization |
|
|
| PANTHER Family | ||
| PANTHER Subfamily | ||
| PANTHER Protein Class | ||
| PANTHER Pathway Category | No pathway information available | |
6 GO annotations of cellular component
| Name | Definition |
|---|---|
| cytoplasm | The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. |
| cytosol | The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes. |
| endoplasmic reticulum | The irregular network of unit membranes, visible only by electron microscopy, that occurs in the cytoplasm of many eukaryotic cells. The membranes form a complex meshwork of tubular channels, which are often expanded into slitlike cavities called cisternae. The ER takes two forms, rough (or granular), with ribosomes adhering to the outer surface, and smooth (with no ribosomes attached). |
| Golgi apparatus | A membrane-bound cytoplasmic organelle of the endomembrane system that further processes the core oligosaccharides (e.g. N-glycans) added to proteins in the endoplasmic reticulum and packages them into membrane-bound vesicles. The Golgi apparatus operates at the intersection of the secretory, lysosomal, and endocytic pathways. |
| mitochondrion | A semiautonomous, self replicating organelle that occurs in varying numbers, shapes, and sizes in the cytoplasm of virtually all eukaryotic cells. It is notably the site of tissue respiration. |
| ubiquitin ligase complex | A protein complex that includes a ubiquitin-protein ligase and enables ubiquitin protein ligase activity. The complex also contains other proteins that may confer substrate specificity on the complex. |
4 GO annotations of molecular function
| Name | Definition |
|---|---|
| ubiquitin conjugating enzyme binding | Binding to a ubiquitin conjugating enzyme, any of the E2 proteins. |
| ubiquitin protein ligase activity | Catalysis of the transfer of ubiquitin to a substrate protein via the reaction X-ubiquitin + S -> X + S-ubiquitin, where X is either an E2 or E3 enzyme, the X-ubiquitin linkage is a thioester bond, and the S-ubiquitin linkage is an amide bond |
| ubiquitin-protein transferase activity | Catalysis of the transfer of ubiquitin from one protein to another via the reaction X-Ub + Y --> Y-Ub + X, where both X-Ub and Y-Ub are covalent linkages. |
| zinc ion binding | Binding to a zinc ion (Zn). |
29 GO annotations of biological process
| Name | Definition |
|---|---|
| adult locomotory behavior | Locomotory behavior in a fully developed and mature organism. |
| autophagy of mitochondrion | The autophagic process in which mitochondria are delivered to a type of vacuole and degraded in response to changing cellular conditions. |
| larval locomotory behavior | Locomotory behavior in a larval (immature) organism. |
| mitochondrial fission | The division of a mitochondrion within a cell to form two or more separate mitochondrial compartments. |
| mitochondrion organization | A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a mitochondrion; includes mitochondrial morphogenesis and distribution, and replication of the mitochondrial genome as well as synthesis of new mitochondrial components. |
| negative regulation of JNK cascade | Any process that stops, prevents, or reduces the frequency, rate or extent of signal transduction mediated by the JNK cascade. |
| negative regulation of mitochondrial fusion | Any process that decreases the frequency, rate or extent of merging of two or more mitochondria within a cell to form a single compartment. |
| negative regulation of protein phosphorylation | Any process that stops, prevents or reduces the rate of addition of phosphate groups to amino acids within a protein. |
| neuron cellular homeostasis | The cellular homeostatic process that preserves a neuron in a stable, differentiated functional and structural state. |
| oogenesis | The complete process of formation and maturation of an ovum or female gamete from a primordial female germ cell. Examples of this process are found in Mus musculus and Drosophila melanogaster. |
| parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization | A positive regulation of the macromitophagy pathway that is triggered by mitochondrial depolarization and requires the function of a parkin-family molecule. |
| positive regulation of autophagy of mitochondrion | Any process that activates or increases the frequency, rate or extent of mitochondrion degradation by autophagy. |
| positive regulation of compound eye pigmentation | Any process that activates or increases the frequency, rate or extent of establishment of a pattern of pigment in the compound eye. |
| positive regulation of locomotor rhythm | Any process that activates or increases the frequency, rate or extent of locomotor rhythm. |
| positive regulation of mitochondrial fission | Any process that increases the rate, frequency or extent of mitochondrial fission. Mitochondrial fission is the division of a mitochondrion within a cell to form two or more separate mitochondrial compartments. |
| positive regulation of mitophagy | Any process that activates or increases the frequency, rate or extent of mitophagy. |
| positive regulation of neuronal action potential | Any process that activates or increases the frequency, rate or extent of neuronal action potential. |
| positive regulation of proteasomal ubiquitin-dependent protein catabolic process | Any process that activates or increases the frequency, rate or extent of the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of ubiquitin, and mediated by the proteasome. |
| protein autoubiquitination | The ubiquitination by a protein of one or more of its own amino acid residues, or residues on an identical protein. Ubiquitination occurs on the lysine residue by formation of an isopeptide crosslink. |
| protein monoubiquitination | Addition of a single ubiquitin group to a protein. |
| protein polyubiquitination | Addition of multiple ubiquitin groups to a protein, forming a ubiquitin chain. |
| protein ubiquitination | The process in which one or more ubiquitin groups are added to a protein. |
| regulation of apoptotic process | Any process that modulates the occurrence or rate of cell death by apoptotic process. |
| regulation of cellular response to oxidative stress | Any process that modulates the frequency, rate or extent of cellular response to oxidative stress. |
| regulation of mitochondrion organization | Any process that modulates the frequency, rate or extent of a process involved in the formation, arrangement of constituent parts, or disassembly of a mitochondrion. |
| response to oxidative stress | Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of oxidative stress, a state often resulting from exposure to high levels of reactive oxygen species, e.g. superoxide anions, hydrogen peroxide (H2O2), and hydroxyl radicals. |
| sperm mitochondrion organization | A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of sperm mitochondria; the process in which they take on their characteristic morphology; they are flattened, elongated, and arranged circumferentially into a tight helical coil around the tail-dense fibers of the mature sperm. |
| spermatogenesis | The developmental process by which male germ line stem cells self renew or give rise to successive cell types resulting in the development of a spermatozoa. |
| ubiquitin-dependent protein catabolic process | The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of a ubiquitin group, or multiple ubiquitin groups, to the protein. |
5 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| O76924 | ari-2 | Potential E3 ubiquitin-protein ligase ariadne-2 | Drosophila melanogaster (Fruit fly) | SS |
| Q94981 | ari-1 | E3 ubiquitin-protein ligase ariadne-1 | Drosophila melanogaster (Fruit fly) | SS |
| O60260 | PRKN | E3 ubiquitin-protein ligase parkin | Homo sapiens (Human) | EV |
| Q9WVS6 | Prkn | E3 ubiquitin-protein ligase parkin | Mus musculus (Mouse) | EV SS |
| Q9JK66 | Prkn | E3 ubiquitin-protein ligase parkin | Rattus norvegicus (Rat) | EV SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MSFIFKFIAT | FVRKMLELLQ | FGGKTLTHTL | SIYVKTNTGK | TLTVNLEPQW | DIKNVKELVA |
| 70 | 80 | 90 | 100 | 110 | 120 |
| PQLGLQPDDL | KIIFAGKELS | DATTIEQCDL | GQQSVLHAIR | LRPPVQRQKI | QSATLEEEEP |
| 130 | 140 | 150 | 160 | 170 | 180 |
| SLSDEASKPL | NETLLDLQLE | SEERLNITDE | ERVRAKAHFF | VHCSQCDKLC | NGKLRVRCAL |
| 190 | 200 | 210 | 220 | 230 | 240 |
| CKGGAFTVHR | DPECWDDVLK | SRRIPGHCES | LEVACVDNAA | GDPPFAEFFF | KCAEHVSGGE |
| 250 | 260 | 270 | 280 | 290 | 300 |
| KDFAAPLNLI | KNNIKNVPCL | ACTDVSDTVL | VFPCASQHVT | CIDCFRHYCR | SRLGERQFMP |
| 310 | 320 | 330 | 340 | 350 | 360 |
| HPDFGYTLPC | PAGCEHSFIE | EIHHFKLLTR | EEYDRYQRFA | TEEYVLQAGG | VLCPQPGCGM |
| 370 | 380 | 390 | 400 | 410 | 420 |
| GLLVEPDCRK | VTCQNGCGYV | FCRNCLQGYH | IGECLPEGTG | ASATNSCEYT | VDPNRAAEAR |
| 430 | 440 | 450 | 460 | 470 | 480 |
| WDEASNVTIK | VSTKPCPKCR | TPTERDGGCM | HMVCTRAGCG | FEWCWVCQTE | WTRDCMGAHW |
| FG |