Crystal structure of a phosphorylated Smad2:: Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-β signaling
Crystal structure of a phosphorylated Smad2:: Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-β signaling
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DOI：
10.1016/s1097-2765(01)00421-x
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发表时间：
2001-12-01
期刊：
影响因子：
16
通讯作者：
Shi, YG
中科院分区：
文献类型：
--
作者：
Wu, JW;Hu, M;Shi, YG
配体诱导的受体调节的Smads(R-Smads)的磷酸化在受体Ser/Thr激酶介导的转化生长因子-β信号转导中起着至关重要的作用。在1.8埃分辨率下，磷酸化的Smad2的晶体结构揭示了C-末端磷酸丝氨酸(PSer)残基介导的同源三聚体的形成。MH2结构域上的pSer结合表面在癌症中经常被认为是失活的，在Co-Smad和R-Smad之间高度保守。这一发现与突变数据一起，确定了Smad2和Smad4之间的功能接口。此外，MH2结构域上的pSer结合表面与R-SMADs上的表面一致，后者是与丝氨酸磷酸化受体激酶对接所必需的。这些观察结果确定了MH2结构域在受体Ser/Thr激酶信号通路中作为pSer-X-pSer结合模块的双功能作用。
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 Angstrom 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.