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Protein ubiquitination patterns are an important component of cellular signaling. The WD-repeat protein WDR48 (USP1-associated factor UAF-1) stimulates activity of ubiquitin-specific proteases USP1, USP12, and USP46. To understand how WDR48 exerts its effect on the USP scaffold, we determined structures of the ternary WDR48:USP46:ubiquitin complex. WDR48 interacts with the USP46 fingers subdomain via a relatively small, highly polar surface on the top center of the WDR48 β propeller. In addition, WDR48 has a novel ancillary domain and a C-terminal SUMO-like domain encircling the USP46-bound ubiquitin. Mutation of residues involved in the WDR48:USP46 interaction abrogated both binding and deubiquitinase activity of the complex. An analogous mutation in USP1 similarly blocked WDR48-dependent activation. Our data suggest a possible mechanism of deubiquitinase stimulation via stabilization and prolonged residence time of substrate. The unprecedented mode of interaction between the USP fingers domain and the WD-repeat β propeller serves as a prototypical example for this family of deubiquitinases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Citation

Jianping Yin, Allyn J Schoeffler, Katherine Wickliffe, Kim Newton, Melissa A Starovasnik, Erin C Dueber, Seth F Harris. Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46. Structure (London, England : 1993). 2015 Nov 3;23(11):2043-54

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PMID: 26388029

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