Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway
Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway
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DOI：
10.1073/pnas.0610716104
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发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Cheong, Chaejoon
中科院分区：
文献类型：
--
作者：
Hwang, Eunha;Ryu, Kyoung-Seok;Cheong, Chaejoon
在真核细胞中，Ras -> RASSF -> MST 途径的细胞凋亡和细胞周期停滞是由肿瘤抑制蛋白 C 末端部分 SARAH（代表 Salvador/Rassf/Hippo）结构域的相互作用控制的。 Mst1 SARAH 结构域通过形成介导细胞凋亡过程的异二聚体，与其 Rassf1 和 Rassf5（也称为 Nore1）的同源结构域相互作用。在这里，我们描述了人类 Mst1 SARAH 结构域的同二聚体结构及其与 Rassf5 和 Salvador (Sav) SARAH 结构域的异型相互作用。 Mst1 SARAH 结构形成每个单体含有两个螺旋的同二聚体。长 α 螺旋 (h2/h2') 的反平行排列在两个单体之间提供了细长的结合界面，短 3(10) 螺旋 (h1/h1') 向另一个单体的螺旋折叠。化学位移扰动实验确定了与 Rassf5 SARAH 结构域的细长紧密结合界面和 1:1 异二聚体形成。游离蛋白中激酶和 SARAH 结构域之间的连接区显示无序。这些结果意味着与 RASSF 家族蛋白相互作用的新模式，并提供了对 SARAH 结构域控制细胞凋亡的机制的深入了解。
In eukaryotic cells, apoptosis and cell cycle arrest by the Ras -> RASSF -> MST pathway are controlled by the interaction of SARAH (for Salvador/Rassf /Hippo) domains in the C-terminal part of tumor suppressor proteins. The Mst1 SARAH domain interacts with its homologous domain of Rassf1 and Rassf5 (also known as Nore1) by forming a heterodimer that mediates the apoptosis process. Here, we describe the homodimeric structure of the human Mst1 SARAH domain and its heterotypic interaction with the Rassf5 and Salvador (Sav) SARAH domain. The Mst1 SARAH structure forms a homodimer containing two helices per monomer. An antiparallel arrangement of the long alpha-helices (h2/h2 ') provides an elongated binding interface between the two monomers, and the short 3(10) helices (h1/h1 ') are folded toward that of the other monomer. Chemical shift perturbation experiments identified an elongated, tight-binding interface with the Rassf5 SARAH domain and a 1:1 heterodimer formation. The linker region between the kinase and the SARAH domain is shown to be disordered in the free protein. These results imply a novel mode of interaction with RASSF family proteins and provide insight into the mechanism of apoptosis control by the SARAH domain.