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PMID: 22885007 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases.

Molecular cell ·Vol. 47 ·No. 6 ·2012-09-28 ·Pages 933-42

Pruneda JN, Littlefield PJ, Soss SE, Nordquist KA, Chazin WJ, Brzovic PS, Klevit RE

Abstract

Despite the widespread importance of RING/U-box E3 ubiquitin ligases in ubiquitin (Ub) signaling, the mechanism by which this class of enzymes facilitates Ub transfer remains enigmatic. Here, we present a structural model for a RING/U-box E3:E2~Ub complex poised for Ub transfer. The model and additional analyses reveal that E3 binding biases dynamic E2~Ub ensembles toward closed conformations with enhanced reactivity for substrate lysines. We identify a key hydrogen bond between a highly conserved E3 side chain and an E2 backbone carbonyl, observed in all structures of active RING/U-Box E3/E2 pairs, as the linchpin for allosteric activation of E2~Ub. The conformational biasing mechanism is generalizable across diverse E2s and RING/U-box E3s, but is not shared by HECT-type E3s. The results provide a structural model for a RING/U-box E3:E2~Ub ligase complex and identify the long sought-after source of allostery for RING/U-Box activation of E2~Ub conjugates.

MeSH Terms
Crystallography, X-Ray Hydrogen Bonding Protein Binding Protein Conformation Protein Subunits/chemistry,metabolism Signal Transduction Ubiquitin/chemistry,metabolism Ubiquitin-Conjugating Enzymes/chemistry,metabolism Ubiquitin-Protein Ligases/chemistry,metabolism
Chemicals
Protein Subunits Ubiquitin Ubiquitin-Conjugating Enzymes Ubiquitin-Protein Ligases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Pruneda Jonathan N
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Littlefield Peter J
Soss Sarah E
Nordquist Kyle A
Chazin Walter J
Brzovic Peter S
Klevit Rachel E
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2012.07.001
Published
2012-09-28
Epub
2012-00-09
Pages
933-42
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3462262
Subset
IM
Grants
NCRR NIH HHS · S10 RR019133 · United States
NCI NIH HHS · T32 CA009582 · United States
NIGMS NIH HHS · 2T32 GM007270 · United States
NIEHS NIH HHS · P30 ES0000267 · United States
NIGMS NIH HHS · T32 GM007270 · United States
NCI NIH HHS · P30 CA068485 · United States
NIGMS NIH HHS · R01 GM098503 · United States
NIEHS NIH HHS · P30 ES000267 · United States
NCI NIH HHS · P50 CA068485 · United States
NIGMS NIH HHS · R01 GM075156 · United States
NIGMS NIH HHS · R01 GM088055 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2012.07.001 PMC Full Text View journal details
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