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Nat Struct Mol Biol. 2015 Mar;22(3):222-9. doi: 10.1038/nsmb.2970. Epub 2015 Feb 16.

Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity.

Author information

1
1] Life Science Division, Synchrotron Radiation Research Organization, University of Tokyo, Tokyo, Japan. [2] Center for Structural Biology of Challenging Proteins, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan. [3] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
2
Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
3
Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
4
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
5
1] Division of Cellular and Molecular Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [2] Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
6
1] Life Science Division, Synchrotron Radiation Research Organization, University of Tokyo, Tokyo, Japan. [2] Center for Structural Biology of Challenging Proteins, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan. [3] Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan. [4] Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.

Abstract

The tumor suppressor CYLD belongs to a ubiquitin (Ub)-specific protease (USP) family and specifically cleaves Met1- and Lys63-linked polyubiquitin chains to suppress inflammatory signaling pathways. Here, we report crystal structures representing the catalytic states of zebrafish CYLD for Met1- and Lys63-linked Ub chains and two distinct precatalytic states for Met1-linked chains. In both catalytic states, the distal Ub is bound to CYLD in a similar manner, and the scissile bond is located close to the catalytic residue, whereas the proximal Ub is bound in a manner specific to Met1- or Lys63-linked chains. Further structure-based mutagenesis experiments support the mechanism by which CYLD specifically cleaves both Met1- and Lys63-linked chains and provide insight into tumor-associated mutations of CYLD. This study provides new structural insight into the mechanisms by which USP family deubiquitinating enzymes recognize and cleave Ub chains with specific linkage types.

PMID:
25686088
DOI:
10.1038/nsmb.2970
[Indexed for MEDLINE]

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