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Ubiquitin chain conformation regulates recognition and activity of interacting proteins

Title: Ubiquitin chain conformation regulates recognition and activity of interacting proteins
Authors: Ye, Y
Blaser, G
Horrocks, MH
Ruedas-Rama, MJ
Ibrahim, S
Zhukov, AA
Orte, A
Klenerman, D
Jackson, SE
Komander, D
Item Type: Journal Article
Abstract: Mechanisms of protein recognition have been extensively studied for single-domain proteins1, but are less well characterized for dynamic multidomain systems. Ubiquitin chains represent a biologically important multidomain system that requires recognition by structurally diverse ubiquitin-interacting proteins2,3. Ubiquitin chain conformations in isolation are often different from conformations observed in ubiquitin-interacting protein complexes, indicating either great dynamic flexibility or extensive chain remodelling upon binding. Using single-molecule fluorescence resonance energy transfer, we show that Lys 63-, Lys 48- and Met 1-linked diubiquitin exist in several distinct conformational states in solution. Lys 63- and Met 1-linked diubiquitin adopt extended ‘open’ and more compact ‘closed’ conformations, and ubiquitin-binding domains and deubiquitinases (DUBs) select pre-existing conformations. By contrast, Lys 48-linked diubiquitin adopts predominantly compact conformations. DUBs directly recognize existing conformations, but may also remodel ubiquitin chains to hydrolyse the isopeptide bond. Disruption of the Lys 48–diubiquitin interface changes conformational dynamics and affects DUB activity. Hence, conformational equilibria in ubiquitin chains provide an additional layer of regulation in the ubiquitin system, and distinct conformations observed in differently linked polyubiquitin may contribute to the specificity of ubiquitin-interacting proteins.
Issue Date: 13-Dec-2012
Date of Acceptance: 25-Oct-2012
URI: http://hdl.handle.net/10044/1/81670
DOI: 10.1038/nature11722
ISSN: 0028-0836
Publisher: Nature Research
Start Page: 266
End Page: 270
Journal / Book Title: Nature
Volume: 492
Issue: 7428
Copyright Statement: ©2012 Macmillan Publishers Limited. All rights reserved.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
FLUORESCENCE COINCIDENCE SPECTROSCOPY
LINEAR POLYUBIQUITIN CHAINS
KAPPA-B ACTIVATION
SINGLE-MOLECULE
STRUCTURAL BASIS
DIUBIQUITIN
BINDING
NMR
E2
Fluorescence Resonance Energy Transfer
Models, Molecular
Protein Binding
Protein Structure, Tertiary
Ubiquitin
Ubiquitin
Fluorescence Resonance Energy Transfer
Protein Structure, Tertiary
Protein Binding
Models, Molecular
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
FLUORESCENCE COINCIDENCE SPECTROSCOPY
LINEAR POLYUBIQUITIN CHAINS
KAPPA-B ACTIVATION
SINGLE-MOLECULE
STRUCTURAL BASIS
DIUBIQUITIN
BINDING
NMR
E2
General Science & Technology
Publication Status: Published
Online Publication Date: 2012-12-02
Appears in Collections:Department of Brain Sciences