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PMID: 15931224 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex.

Nature ·Vol. 435 ·No. 7042 ·2005-06-02 ·Pages 687-92

Reverter D, Lima CD

Abstract

SUMO-1 (for small ubiquitin-related modifier) belongs to the ubiquitin (Ub) and ubiquitin-like (Ubl) protein family. SUMO conjugation occurs on specific lysine residues within protein targets, regulating pathways involved in differentiation, apoptosis, the cell cycle and responses to stress by altering protein function through changes in activity or cellular localization or by protecting substrates from ubiquitination. Ub/Ubl conjugation occurs in sequential steps and requires the concerted action of E2 conjugating proteins and E3 ligases. In addition to being a SUMO E3, the nucleoporin Nup358/RanBP2 localizes SUMO-conjugated RanGAP1 to the cytoplasmic face of the nuclear pore complex by means of interactions in a complex that also includes Ubc9, the SUMO E2 conjugating protein. Here we describe the 3.0-A crystal structure of a four-protein complex of Ubc9, a Nup358/RanBP2 E3 ligase domain (IR1-M) and SUMO-1 conjugated to the carboxy-terminal domain of RanGAP1. Structural insights, combined with biochemical and kinetic data obtained with additional substrates, support a model in which Nup358/RanBP2 acts as an E3 by binding both SUMO and Ubc9 to position the SUMO-E2-thioester in an optimal orientation to enhance conjugation.

MeSH Terms
Amino Acid Sequence Binding Sites Crystallography, X-Ray GTPase-Activating Proteins/chemistry,metabolism Humans Models, Molecular Molecular Chaperones/chemistry,metabolism Molecular Sequence Data Multiprotein Complexes/chemistry,metabolism Nuclear Pore Complex Proteins/chemistry,metabolism Protein Conformation SUMO-1 Protein/chemistry,metabolism Structure-Activity Relationship Ubiquitin-Conjugating Enzymes/chemistry,metabolism Ubiquitin-Protein Ligases/chemistry,metabolism
Chemicals
GTPase-Activating Proteins Molecular Chaperones Multiprotein Complexes Nuclear Pore Complex Proteins RANGAP1 protein, human SUMO-1 Protein ran-binding protein 2 Ubiquitin-Conjugating Enzymes Ubiquitin-Protein Ligases ubiquitin-conjugating enzyme UBC9
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Reverter David
Structural Biology Program, Sloan-Kettering Institute, New York, New York 10021, USA.
Lima Christopher D
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature03588
Published
2005-06-02
Pages
687-92
Language
English
Region
England
NLM ID
0410462
PMCID
PMC1416492
Subset
IM
Grants
NIGMS NIH HHS · R01 GM065872 · United States
Databases
PDB
1Z5S
External Links
PubMed source DOI: 10.1038/nature03588 PMC Full Text View journal details
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