磷酸化Smad2的晶体结构。MH2结构域对磷酸丝氨酸的识别及对TGF-β信号通路中Smad功能的见解。

Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.

作者信息

Wu J W, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti D J, Kyin S, Muir T W, Fairman R, Massagué J, Shi Y

机构信息

Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA.

出版信息

Mol Cell. 2001 Dec;8(6):1277-89. doi: 10.1016/s1097-2765(01)00421-x.

DOI:10.1016/s1097-2765(01)00421-x

PMID:11779503

Abstract

Ligand-induced phosphorylation of the receptor-regulated Smads (R-Smads) is essential in the receptor Ser/Thr kinase-mediated TGF-beta signaling. The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues. The pSer binding surface on the MH2 domain, frequently targeted for inactivation in cancers, is highly conserved among the Co- and R-Smads. This finding, together with mutagenesis data, pinpoints a functional interface between Smad2 and Smad4. In addition, the pSer binding surface on the MH2 domain coincides with the surface on R-Smads that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations define a bifunctional role for the MH2 domain as a pSer-X-pSer binding module in receptor Ser/Thr kinase signaling pathways.

摘要

配体诱导的受体调节型Smads（R-Smads）磷酸化在受体丝氨酸/苏氨酸激酶介导的TGF-β信号传导中至关重要。分辨率为1.8埃的磷酸化Smad2晶体结构揭示了由C端磷酸丝氨酸（pSer）残基介导形成的同三聚体。MH2结构域上的pSer结合表面在癌症中常成为失活靶点，在共Smads和R-Smads中高度保守。这一发现与诱变数据一起，确定了Smad2和Smad4之间的功能界面。此外，MH2结构域上的pSer结合表面与R-Smads上与丝氨酸磷酸化受体激酶对接相互作用所需的表面重合。这些观察结果确定了MH2结构域在受体丝氨酸/苏氨酸激酶信号通路中作为pSer-X-pSer结合模块的双功能作用。