Journal
MOLECULAR CELL
Volume 29, Issue 4, Pages 451-464Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2007.12.018
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Funding
- EPSRC [EP/D032210/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/D032210/1] Funding Source: researchfish
- Breast Cancer Now [BREAST CANCER NOW RESEARCH CENTRE] Funding Source: Medline
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The tumor suppressor CYLD antagonizes NF-kappa B 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 LISP 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.
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