Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 3, Pages 222-229Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2970
Keywords
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Funding
- CREST, JST
- [22121003]
- [22117002]
- [22117003]
- [22117006]
- [25117711]
- [25112505]
- [24687012]
- [24247014]
- Grants-in-Aid for Scientific Research [25650003, 22117001, 22117003, 24390079, 25670137, 24570126, 22121003, 22117006, 22117002, 26840062] Funding Source: KAKEN
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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.
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