A2A5Z6
SS
Gene name |
Smurf2 |
Protein name |
E3 ubiquitin-protein ligase SMURF2 |
Names |
HECT-type E3 ubiquitin transferase SMURF2, SMAD ubiquitination regulatory factor 2, SMAD-specific E3 ubiquitin-protein ligase 2 |
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:66313 |
EC number |
2.3.2.26: Aminoacyltransferases |
Protein Class |
|
Descriptions
Ubiquitination of proteins is an abundant modification that controls numerous cellular processes. The C2-WW-HECT-domain E3 Smurf2 downregulates transforming growth factor-β (TGF-β) signaling by targeting itself, the adaptor protein Smad7, and TGF-b receptor kinases for degradation. In a human hologous protein, Smurf2 (Q9HAU4), the intramolecular interaction between C2 phospholipid binding domain and HECT domain inhibits the catalytic activity of the HECT domain by obstructing accessibility of the catalytic cysteine of the HECT domain and thus blocking Smurf2-Ub thioester formation.
Autoinhibitory domains (AIDs)
Target domain |
393-748 (HECT domain) |
Relief mechanism |
Partner binding |
Assay |
|
Accessory elements
No accessory elements
References
- Wiesner S et al. (2007) "Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain", Cell, 130, 651-62
- Lu K et al. (2011) "Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection", The Journal of biological chemistry, 286, 16861-70
- Ogunjimi AA et al. (2005) "Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain", Molecular cell, 19, 297-308
- Riling C et al. (2015) "Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation", The Journal of biological chemistry, 290, 23875-87
- Wang Z et al. (2019) "A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases", Nature communications, 10, 3162
- Zhu K et al. (2017) "Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch", EMBO reports, 18, 1618-1630
- Tsunoda T et al. (2022) "ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer", EMBO reports, 23, e51182
- Chen Z et al. (2017) "A Tunable Brake for HECT Ubiquitin Ligases", Molecular cell, 66, 345-357.e6
- Mund T et al. (2009) "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins", EMBO reports, 10, 501-7
Autoinhibited structure
Activated structure
1 structures for A2A5Z6
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-A2A5Z6-F1 | Predicted | AlphaFoldDB |
4 variants for A2A5Z6
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs27039797 | 354 | P>S | No | Ensembl | |
| rs1134046264 | 571 | I>M | No | Ensembl | |
| rs1131878223 | 577 | N>H | No | Ensembl | |
| rs219863736 | 592 | R>Q | No | Ensembl |
No associated diseases with A2A5Z6
Functions
| Description | ||
|---|---|---|
| EC Number | 2.3.2.26 | 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. |
| membrane raft | Any of the small (10-200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched membrane domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein-lipid interactions. |
| nuclear speck | A discrete extra-nucleolar subnuclear domain, 20-50 in number, in which splicing factors are seen to be localized by immunofluorescence microscopy. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
| 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 |
|---|---|
| identical protein binding | Binding to an identical protein or proteins. |
| SMAD binding | Binding to a SMAD signaling protein. |
| 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: an isopeptide bond between the C-terminal glycine of ubiquitin and the epsilon-amino group of lysine residues in the substrate or, in the linear extension of ubiquitin chains, a peptide bond the between the C-terminal glycine and N-terminal methionine of ubiquitin residues. |
| 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. |
9 GO annotations of biological process
| Name | Definition |
|---|---|
| negative regulation of BMP signaling pathway | Any process that stops, prevents, or reduces the frequency, rate or extent of the BMP signaling pathway. |
| negative regulation of transforming growth factor beta receptor signaling pathway | Any process that stops, prevents, or reduces the frequency, rate or extent of any TGF-beta receptor signaling pathway. |
| positive regulation of protein catabolic process | Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the breakdown of a protein by the destruction of the native, active configuration, with or without the hydrolysis of peptide bonds. |
| positive regulation of trophoblast cell migration | Any process that activates or increases the frequency, rate or extent of trophoblast cell migration. |
| proteasome-mediated 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 ubiquitin, and mediated by the proteasome. |
| 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. |
| 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. |
| ubiquitin-dependent SMAD protein catabolic process | The chemical reactions and pathways resulting in the breakdown of SMAD signaling proteins by ubiquitination and targeting to the proteasome. |
23 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| P39940 | RSP5 | E3 ubiquitin-protein ligase RSP5 | Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) | PR |
| Q9Y0H4 | Su(dx) | E3 ubiquitin-protein ligase Su | Drosophila melanogaster (Fruit fly) | SS |
| Q9V853 | Smurf | E3 ubiquitin-protein ligase Smurf1 | Drosophila melanogaster (Fruit fly) | SS |
| O00308 | WWP2 | NEDD4-like E3 ubiquitin-protein ligase WWP2 | Homo sapiens (Human) | EV |
| Q9HCE7 | SMURF1 | E3 ubiquitin-protein ligase SMURF1 | Homo sapiens (Human) | PR |
| O95817 | BAG3 | BAG family molecular chaperone regulator 3 | Homo sapiens (Human) | PR |
| Q96PU5 | NEDD4L | E3 ubiquitin-protein ligase NEDD4-like | Homo sapiens (Human) | PR |
| O60861 | GAS7 | Growth arrest-specific protein 7 | Homo sapiens (Human) | PR |
| P46934 | NEDD4 | E3 ubiquitin-protein ligase NEDD4 | Homo sapiens (Human) | EV |
| Q9H0M0 | WWP1 | NEDD4-like E3 ubiquitin-protein ligase WWP1 | Homo sapiens (Human) | EV |
| Q96J02 | ITCH | E3 ubiquitin-protein ligase Itchy homolog | Homo sapiens (Human) | EV |
| Q9HAU4 | SMURF2 | E3 ubiquitin-protein ligase SMURF2 | Homo sapiens (Human) | EV |
| Q60780 | Gas7 | Growth arrest-specific protein 7 | Mus musculus (Mouse) | PR |
| Q9CUN6 | Smurf1 | E3 ubiquitin-protein ligase SMURF1 | Mus musculus (Mouse) | PR |
| Q8BZZ3 | Wwp1 | NEDD4-like E3 ubiquitin-protein ligase WWP1 | Mus musculus (Mouse) | SS |
| Q8C863 | Itch | E3 ubiquitin-protein ligase Itchy | Mus musculus (Mouse) | EV |
| Q9DBH0 | Wwp2 | NEDD4-like E3 ubiquitin-protein ligase WWP2 | Mus musculus (Mouse) | SS |
| P46935 | Nedd4 | E3 ubiquitin-protein ligase NEDD4 | Mus musculus (Mouse) | PR |
| Q3U0D9 | Hace1 | E3 ubiquitin-protein ligase HACE1 | Mus musculus (Mouse) | SS |
| Q8CFI0 | Nedd4l | E3 ubiquitin-protein ligase NEDD4-like | Mus musculus (Mouse) | PR |
| Q62940 | Nedd4 | E3 ubiquitin-protein ligase NEDD4 | Rattus norvegicus (Rat) | PR |
| Q9N2Z7 | wwp-1 | E3 ubiquitin-protein ligase wwp-1 | Caenorhabditis elegans | SS |
| A9JRZ0 | smurf2 | E3 ubiquitin-protein ligase SMURF2 | Danio rerio (Zebrafish) (Brachydanio rerio) | SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MSNPGGRRNG | PVKLRLTVLC | AKNLVKKDFF | RLPDPFAKVV | VDGSGQCHST | DTVKNTLDPK |
| 70 | 80 | 90 | 100 | 110 | 120 |
| WNQHYDLYIG | KSDSVTISVW | NHKKIHKKQG | AGFLGCVRLL | SNAINRLKDT | GYQRLDLCKL |
| 130 | 140 | 150 | 160 | 170 | 180 |
| GPNDNDTVRG | QIVVSLQSRD | RIGTGGQVVD | CSRLFDNDLP | DGWEERRTAS | GRIQYLNHIT |
| 190 | 200 | 210 | 220 | 230 | 240 |
| RTTQWERPTR | PASEYSSPGR | PLSCFVDENT | PITGTNGATC | GHSSDPRLAE | RRVRSQRHRN |
| 250 | 260 | 270 | 280 | 290 | 300 |
| YMSRTHLHTP | PDLPEGYEQR | TTQQGQVYFL | HTQTGVSTWH | DPRVPRDLSN | INCEELGPLP |
| 310 | 320 | 330 | 340 | 350 | 360 |
| PGWEIRNTAT | GRVYFVDHNN | RTTQFTDPRL | SANLHLVLNR | QNQLKDQQQQ | QVVPLCPDDT |
| 370 | 380 | 390 | 400 | 410 | 420 |
| ECLTVPRYKR | DLVQKLKILR | QELSQQQPQA | GHCRIEVSRE | EIFEESYRQV | MKMRPKDLWK |
| 430 | 440 | 450 | 460 | 470 | 480 |
| RLMIKFRGEE | GLDYGGVARE | WLYLLSHEML | NPYYGLFQYS | RDDIYTLQIN | PDSAVNPEHL |
| 490 | 500 | 510 | 520 | 530 | 540 |
| SYFHFVGRIM | GMAVFHGHYI | DGGFTLPFYK | QLLGKSITLD | DMELVDPDLH | NSLVWILEND |
| 550 | 560 | 570 | 580 | 590 | 600 |
| ITGVLDHTFC | VEHNAYGEII | QHELKPNGKS | IPVTEENKKE | YVRLYVNWRF | LRGIEAQFLA |
| 610 | 620 | 630 | 640 | 650 | 660 |
| LQKGFNEVIP | QHLLKTFDEK | ELELIICGLG | KIDVSDWKVN | TRLKHCTPDS | NVVKWFWKAV |
| 670 | 680 | 690 | 700 | 710 | 720 |
| EFFDEERRAR | LLQFVTGSSR | VPLQGFKALQ | GAAGPRLFTI | HQIDACTNNL | PKAHTCFNRI |
| 730 | 740 | ||||
| DIPPYESYEK | LYEKLLTAIE | ETCGFAVE |