Molecular Cell
Volume 29, Issue 4, 29 February 2008, Pages 451-464
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Article
The Structure of the CYLD USP Domain Explains Its Specificity for Lys63-Linked Polyubiquitin and Reveals a B Box Module

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Summary

The tumor suppressor CYLD antagonizes NF-κB and JNK signaling by disassembly of Lys63-linked ubiquitin chains synthesized in response to cytokine stimulation. Here we describe the crystal structure of the CYLD USP domain, revealing a distinctive architecture that provides molecular insights into its specificity toward Lys63-linked polyubiquitin. We identify regions of the USP domain responsible for this specificity and demonstrate endodeubiquitinase activity toward such chains. Pathogenic truncations of the CYLD C terminus, associated with the hypertrophic skin tumor cylindromatosis, disrupt the USP domain, accounting for loss of CYLD catalytic activity. A small zinc-binding B box domain, similar in structure to other crossbrace Zn-binding folds—including the RING domain found in E3 ubiquitin ligases—is inserted within the globular core of the USP domain. Biochemical and functional characterization of the B box suggests a role as a protein-interaction module that contributes to determining the subcellular localization of CYLD.

PROTEINS

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