| Structural highlights
Function
[APC11_HUMAN] Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.[1] [2] [UBB_HUMAN] 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.[3] [4]
Publication Abstract from PubMed
Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination. The APC/C RING constrains UBE2C proximal to a substrate and simultaneously binds a substrate-linked UB to drive processive multiubiquitination. Alternatively, during UB chain elongation, the RING does not bind UBE2S but rather lures an evolving substrate-linked UB to UBE2S positioned through a cullin interaction to generate a Lys11-linked chain. Our findings define mechanisms of APC/C regulation, and establish principles by which specialized E3-E2-substrate-UB architectures control different forms of polyubiquitination.
Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.,Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A, Wu KP, Zhang W, Yu S, Mercredi PY, Harrison JS, Davidson IF, Qiao R, Lu Y, Dube P, Brunner MR, Grace CR, Miller DJ, Haselbach D, Jarvis MA, Yamaguchi M, Yanishevski D, Petzold G, Sidhu SS, Kuhlman B, Kirschner MW, Harper JW, Peters JM, Stark H, Schulman BA Cell. 2016 Jun 2;165(6):1440-53. doi: 10.1016/j.cell.2016.05.037. PMID:27259151[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tang Z, Li B, Bharadwaj R, Zhu H, Ozkan E, Hakala K, Deisenhofer J, Yu H. APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Mol Biol Cell. 2001 Dec;12(12):3839-51. PMID:11739784
- ↑ Jin L, Williamson A, Banerjee S, Philipp I, Rape M. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell. 2008 May 16;133(4):653-65. doi: 10.1016/j.cell.2008.04.012. PMID:18485873 doi:http://dx.doi.org/10.1016/j.cell.2008.04.012
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A, Wu KP, Zhang W, Yu S, Mercredi PY, Harrison JS, Davidson IF, Qiao R, Lu Y, Dube P, Brunner MR, Grace CR, Miller DJ, Haselbach D, Jarvis MA, Yamaguchi M, Yanishevski D, Petzold G, Sidhu SS, Kuhlman B, Kirschner MW, Harper JW, Peters JM, Stark H, Schulman BA. Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C. Cell. 2016 Jun 2;165(6):1440-53. doi: 10.1016/j.cell.2016.05.037. PMID:27259151 doi:http://dx.doi.org/10.1016/j.cell.2016.05.037
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