| Structural highlights
6djx is a 3 chain structure with sequence from Bacdo, Bos taurus and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| NonStd Res: | |
| Gene: | PRKN2 (BACDO), UBE2L3, UBCE7, UBCH7 (HUMAN) |
| Activity: | RBR-type E3 ubiquitin transferase, with EC number 2.3.2.31 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[UB2L3_HUMAN] Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases. Does not function with most RING-containing E3 ubiquitin-protein ligases because it lacks intrinsic E3-independent reactivity with lysine: in contrast, it has activity with the RBR family E3 enzymes, such as PARK2 and ARIH1, that function like function like RING-HECT hybrids. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-linked polyubiquitination. Involved in the selective degradation of short-lived and abnormal proteins. Down-regulated during the S-phase it is involved in progression through the cell cycle. Regulates nuclear hormone receptors transcriptional activity. May play a role in myelopoiesis.[1] [2] [3] [4] [5] [6] [7] [RS27A_BOVIN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity). Ribosomal protein S27a is a component of the 40S subunit of the ribosome.
Publication Abstract from PubMed
Mutations in the ubiquitin ligase parkin are responsible for a familial form of Parkinson's disease. Parkin and the PINK1 kinase regulate a quality-control system for mitochondria. PINK1 phosphorylates ubiquitin on the outer membrane of damaged mitochondria, thus leading to recruitment and activation of parkin via phosphorylation of its ubiquitin-like (Ubl) domain. Here, we describe the mechanism of parkin activation by phosphorylation. The crystal structure of phosphorylated Bactrocera dorsalis (oriental fruit fly) parkin in complex with phosphorylated ubiquitin and an E2 ubiquitin-conjugating enzyme reveals that the key activating step is movement of the Ubl domain and release of the catalytic RING2 domain. Hydrogen/deuterium exchange and NMR experiments with the various intermediates in the activation pathway confirm and extend the interpretation of the crystal structure to mammalian parkin. Our results rationalize previously unexplained Parkinson's disease mutations and the presence of internal linkers that allow large domain movements in parkin.
Mechanism of parkin activation by phosphorylation.,Sauve V, Sung G, Soya N, Kozlov G, Blaimschein N, Miotto LS, Trempe JF, Lukacs GL, Gehring K Nat Struct Mol Biol. 2018 Jul;25(7):623-630. doi: 10.1038/s41594-018-0088-7. Epub, 2018 Jul 2. PMID:29967542[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000 Jul;25(3):302-5. PMID:10888878 doi:10.1038/77060
- ↑ Verma S, Ismail A, Gao X, Fu G, Li X, O'Malley BW, Nawaz Z. The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors. Mol Cell Biol. 2004 Oct;24(19):8716-26. PMID:15367689 doi:10.1128/MCB.24.19.8716-8726.2004
- ↑ Garside H, Waters C, Berry A, Rice L, Ardley HC, White A, Robinson PA, Ray D. UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation. J Endocrinol. 2006 Sep;190(3):621-9. PMID:17003263 doi:10.1677/joe.1.06799
- ↑ Marteijn JA, van der Meer LT, Smit JJ, Noordermeer SM, Wissink W, Jansen P, Swarts HG, Hibbert RG, de Witte T, Sixma TK, Jansen JH, van der Reijden BA. The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and Ubc13 interacting domains. Leukemia. 2009 Aug;23(8):1480-9. Epub 2009 Apr 2. PMID:19340006 doi:leu200957
- ↑ Whitcomb EA, Dudek EJ, Liu Q, Taylor A. Novel control of S phase of the cell cycle by ubiquitin-conjugating enzyme H7. Mol Biol Cell. 2009 Jan;20(1):1-9. doi: 10.1091/mbc.E08-01-0036. Epub 2008 Oct, 22. PMID:18946090 doi:10.1091/mbc.E08-01-0036
- ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
- ↑ Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature. 2011 Jun 2;474(7349):105-8. doi: 10.1038/nature09966. Epub 2011 May 1. PMID:21532592 doi:10.1038/nature09966
- ↑ Sauve V, Sung G, Soya N, Kozlov G, Blaimschein N, Miotto LS, Trempe JF, Lukacs GL, Gehring K. Mechanism of parkin activation by phosphorylation. Nat Struct Mol Biol. 2018 Jul;25(7):623-630. doi: 10.1038/s41594-018-0088-7. Epub, 2018 Jul 2. PMID:29967542 doi:http://dx.doi.org/10.1038/s41594-018-0088-7
|
