Kristariyanto Yosua Adi, Abdul Rehman Syed Arif, Weidlich Simone, Knebel Axel, Kulathu Yogesh
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
EMBO Rep. 2017 Mar;18(3):392-402. doi: 10.15252/embr.201643205. Epub 2017 Jan 12.
The eight different types of ubiquitin (Ub) chains that can be formed play important roles in diverse cellular processes. Linkage-selective recognition of Ub chains by Ub-binding domain (UBD)-containing proteins is central to coupling different Ub signals to specific cellular responses. The motif interacting with ubiquitin (MIU) is a small UBD that has been characterized for its binding to monoUb. The recently discovered deubiquitinase MINDY-1/FAM63A contains a tandem MIU repeat (tMIU) that is highly selective at binding to K48-linked polyUb. We here identify that this linkage-selective binding is mediated by a single MIU motif (MIU2) in MINDY-1. The crystal structure of MIU2 in complex with K48-linked polyubiquitin chains reveals that MIU2 on its own binds to all three Ub moieties in an open conformation that can only be accommodated by K48-linked triUb. The weak Ub binder MIU1 increases overall affinity of the tMIU for polyUb chains without affecting its linkage selectivity. Our analyses reveal new concepts for linkage selectivity and polyUb recognition by UBDs.
可形成的八种不同类型的泛素（Ub）链在多种细胞过程中发挥重要作用。含泛素结合结构域（UBD）的蛋白质对Ub链的连接选择性识别是将不同Ub信号与特定细胞反应相偶联的核心。与泛素相互作用的基序（MIU）是一种小的UBD，其已被表征为可与单泛素结合。最近发现的去泛素化酶MINDY-1/FAM63A包含一个串联MIU重复序列（tMIU），该序列在结合K48连接的多聚泛素时具有高度选择性。我们在此确定，这种连接选择性结合是由MINDY-1中的单个MIU基序（MIU2）介导的。MIU2与K48连接的多聚泛素链复合物的晶体结构表明，MIU2自身以开放构象结合所有三个Ub部分，而这种构象只能被K48连接的三聚泛素所容纳。弱Ub结合剂MIU1增加了tMIU对多聚泛素链的总体亲和力，而不影响其连接选择性。我们的分析揭示了UBDs对连接选择性和多聚泛素识别的新概念。
