CYLD USP 与 Met1-或 Lys63-连接的二泛素的结构揭示了双重特异性的机制。
Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity.
机构信息
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.
Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
出版信息
Nat Struct Mol Biol. 2015 Mar;22(3):222-9. doi: 10.1038/nsmb.2970. Epub 2015 Feb 16.
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.
肿瘤抑制因子 CYLD 属于泛素 (Ub)-特异性蛋白酶 (USP) 家族，可特异性切割 Met1-和 Lys63 连接的多泛素链，从而抑制炎症信号通路。在此，我们报告了代表斑马鱼 CYLD 切割 Met1-和 Lys63 连接的 Ub 链的催化态以及两种不同的 Met1 连接链的前催化态的晶体结构。在这两种催化态中，远端 Ub 以相似的方式与 CYLD 结合，且切割键靠近催化残基，而近端 Ub 以特定于 Met1-或 Lys63 连接链的方式结合。进一步的基于结构的突变实验支持了 CYLD 特异性切割 Met1-和 Lys63 连接链的机制，并为 CYLD 的肿瘤相关突变提供了见解。这项研究为 USP 家族去泛素化酶识别和切割具有特定连接类型的 Ub 链的机制提供了新的结构见解。
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