PUBLICATION
Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity
- Authors
- Sato, Y., Goto, E., Shibata, Y., Kubota, Y., Yamagata, A., Goto-Ito, S., Kubota, K., Inoue, J.I., Takekawa, M., Tokunaga, F., Fukai, S.
- ID
- ZDB-PUB-150217-1
- Date
- 2015
- Source
- Nature structural & molecular biology 22(3): 222-9 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Ubiquitin Thiolesterase/chemistry
- HEK293 Cells
- Crystallography, X-Ray
- Protein Structure, Tertiary
- Conserved Sequence
- Humans
- Kinetics
- Models, Molecular
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/metabolism
- Tumor Suppressor Proteins/chemistry*
- Tumor Suppressor Proteins/metabolism
- Ubiquitin-Specific Proteases/chemistry*
- Ubiquitin-Specific Proteases/metabolism
- Signal Transduction
- Sequence Analysis, Protein
- Binding Sites
- PubMed
- 25686088 Full text @ Nat. Struct. Mol. Biol.
Citation
Sato, Y., Goto, E., Shibata, Y., Kubota, Y., Yamagata, A., Goto-Ito, S., Kubota, K., Inoue, J.I., Takekawa, M., Tokunaga, F., Fukai, S. (2015) Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity. Nature structural & molecular biology. 22(3):222-9.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping