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PMID: 21376237 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

The mechanism of linkage-specific ubiquitin chain elongation by a single-subunit E2.

Cell ·Vol. 144 ·No. 5 ·2011-03-04 ·Pages 769-81

Wickliffe KE, Lorenz S, Wemmer DE, Kuriyan J, Rape M

Abstract

Ubiquitin chains of different topologies trigger distinct functional consequences, including protein degradation and reorganization of complexes. The assembly of most ubiquitin chains is promoted by E2s, yet how these enzymes achieve linkage specificity is poorly understood. We have discovered that the K11-specific Ube2S orients the donor ubiquitin through an essential noncovalent interaction that occurs in addition to the thioester bond at the E2 active site. The E2-donor ubiquitin complex transiently recognizes the acceptor ubiquitin, primarily through electrostatic interactions. The recognition of the acceptor ubiquitin surface around Lys11, but not around other lysines, generates a catalytically competent active site, which is composed of residues of both Ube2S and ubiquitin. Our studies suggest that monomeric E2s promote linkage-specific ubiquitin chain formation through substrate-assisted catalysis.

MeSH Terms
Catalysis Humans Hydrophobic and Hydrophilic Interactions Models, Molecular Ubiquitin/chemistry,metabolism Ubiquitin-Conjugating Enzymes/chemistry,metabolism
Chemicals
Ubiquitin Ube2S protein, human Ubiquitin-Conjugating Enzymes
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wickliffe Katherine E
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Lorenz Sonja
Wemmer David E
Kuriyan John
Rape Michael
References (32)
32 references, click to expand
  1. UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit.
    Nat Cell Biol. 2009 Nov;11(11):1363-9 PMID: 19820702
  2. Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.
    Oncogene. 2004 Aug 26;23(39):6621-9 PMID: 15208666
  3. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways.
    Nat Rev Mol Cell Biol. 2009 May;10(5):319-31 PMID: 19352404
  4. Ubiquitin-binding domains - from structures to functions.
    Nat Rev Mol Cell Biol. 2009 Oct;10(10):659-71 PMID: 19773779
  5. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex.
    Nature. 2005 Jun 2;435(7042):687-92 PMID: 15931224
  6. UBE2S drives elongation of K11-linked ubiquitin chains by the anaphase-promoting complex.
    Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1355-60 PMID: 20080579
  7. Identification of conjugation specificity determinants unmasks vestigial preference for ubiquitin within the NEDD8 E2.
    Nat Struct Mol Biol. 2008 Mar;15(3):280-7 PMID: 18264111
  8. Detection of sequential polyubiquitylation on a millisecond timescale.
    Nature. 2009 Dec 3;462(7273):615-9 PMID: 19956254
  9. The processivity of multiubiquitination by the APC determines the order of substrate degradation.
    Cell. 2006 Jan 13;124(1):89-103 PMID: 16413484
  10. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis.
    Nat Med. 2006 Jul;12(7):809-16 PMID: 16819549
  11. Structure of a conjugating enzyme-ubiquitin thiolester intermediate reveals a novel role for the ubiquitin tail.
    Structure. 2001 Oct;9(10):897-904 PMID: 11591345
  12. Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer.
    Cell. 2001 Jun 15;105(6):711-20 PMID: 11440714
  13. Regulated degradation of spindle assembly factors by the anaphase-promoting complex.
    Mol Cell. 2010 May 14;38(3):369-82 PMID: 20471943
  14. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne.
    Nat Struct Mol Biol. 2010 Aug;17(8):939-47 PMID: 20622874
  15. E3-independent monoubiquitination of ubiquitin-binding proteins.
    Mol Cell. 2007 Jun 22;26(6):891-8 PMID: 17588522
  16. On the role of electrostatic interactions in the design of protein-protein interfaces.
    J Mol Biol. 2002 Apr 19;318(1):161-77 PMID: 12054776
  17. Building ubiquitin chains: E2 enzymes at work.
    Nat Rev Mol Cell Biol. 2009 Nov;10(11):755-64 PMID: 19851334
  18. RING domain E3 ubiquitin ligases.
    Annu Rev Biochem. 2009;78:399-434 PMID: 19489725
  19. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.
    Cell. 2008 May 16;133(4):653-65 PMID: 18485873
  20. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains.
    EMBO Rep. 2009 May;10(5):466-73 PMID: 19373254
  21. K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody.
    Mol Cell. 2010 Aug 13;39(3):477-84 PMID: 20655260
  22. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.
    Cell. 2009 Apr 3;137(1):133-45 PMID: 19345192
  23. The anaphase promoting complex/cyclosome: a machine designed to destroy.
    Nat Rev Mol Cell Biol. 2006 Sep;7(9):644-56 PMID: 16896351
  24. Identification of a physiological E2 module for the human anaphase-promoting complex.
    Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18213-8 PMID: 19822757
  25. Mechanistic insights into active site-associated polyubiquitination by the ubiquitin-conjugating enzyme Ube2g2.
    Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3722-7 PMID: 19223579
  26. HADDOCK versus HADDOCK: new features and performance of HADDOCK2.0 on the CAPRI targets.
    Proteins. 2007 Dec 1;69(4):726-33 PMID: 17803234
  27. Ubiquitin-specific protease 2 as a tool for quantification of total ubiquitin levels in biological specimens.
    Anal Biochem. 2006 Jun 1;353(1):153-5 PMID: 16643835
  28. Lysine activation and functional analysis of E2-mediated conjugation in the SUMO pathway.
    Nat Struct Mol Biol. 2006 Jun;13(6):491-9 PMID: 16732283
  29. Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34.
    Cell. 2005 Dec 16;123(6):1107-20 PMID: 16360039
  30. ClusPro: performance in CAPRI rounds 6-11 and the new server.
    Proteins. 2007 Dec 1;69(4):781-5 PMID: 17876812
  31. Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT(NEDD4L) complex.
    Mol Cell. 2009 Dec 25;36(6):1095-102 PMID: 20064473
  32. Mms2-Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation.
    Nat Struct Mol Biol. 2006 Oct;13(10):915-20 PMID: 16980971
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2011.01.035
Published
2011-03-04
Pages
769-81
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3072108
Subset
IM
Grants
NIGMS NIH HHS · GM68933 · United States
NIGMS NIH HHS · GM83064 · United States
NIGMS NIH HHS · P41 GM068933 · United States
NIGMS NIH HHS · R01 GM083064 · United States
NIGMS NIH HHS · R01 GM083064-03 · United States
NIH HHS · DP2 OD003088-01 · United States
NIGMS NIH HHS · NIH-GM 68933 · United States
NCRR NIH HHS · RR15756 · United States
NIH HHS · DP2 OD003088 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2011.01.035 PMC Full Text View journal details
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