Structures of CYLD USP with Met1-or Lys63-linked diubiquitin reveal mechanisms for dual specificity
Structures of CYLD USP with Met1-or Lys63-linked diubiquitin reveal mechanisms for dual specificity
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DOI：
10.1038/nsmb.2970
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发表时间：
2015-03-01
影响因子：
16.8
通讯作者：
Fukai, Shuya
中科院分区：
文献类型：
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作者：
Sato, Yusuke;Goto, Eiji;Fukai, Shuya
肿瘤抑制因子 CYLD 属于泛素 (Ub) 特异性蛋白酶 (USP) 家族，可特异性裂解 Met1 和 Lys63 连接的多聚泛素链以抑制炎症信号传导通路。在这里，我们报道了代表斑马鱼CYLD对Met1和Lys63连接的Ub链的催化状态以及Met1连接的链的两种不同的预催化状态的晶体结构。在两种催化状态下，远端 Ub 以类似的方式与 CYLD 结合，并且易断裂键位于催化残基附近，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诱变实验支持 CYLD 特异性切割 Met1 和 Lys63 连接链的机制，并提供对 CYLD 肿瘤相关突变的深入了解。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。
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.