PH domain of ELMO functions in trans to regulate Rac activation via Dock180
PH domain of ELMO functions in trans to regulate Rac activation via Dock180
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DOI：
10.1038/nsmb800
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发表时间：
2004-08-01
影响因子：
16.8
通讯作者：
Ravichandran, KS
中科院分区：
文献类型：
--
作者：
Lu, MJ;Kinchen, JM;Ravichandran, KS
Dock 180蛋白超家族的成员是Rho家族GTP酶的新型鸟嘌呤核苷酸交换因子（GEF），并且与从蠕虫到哺乳动物的多种生物学过程相关联。埃尔莫是Dock 180的关键调节因子，并且Dock 180-埃尔莫复合物充当Rac的二分GEF。我们鉴定了一种机制，其中埃尔莫的PH结构域通过反式结合Dock 180- Rac复合物使Rac稳定在无核苷酸过渡态。诱变研究揭示，这种埃尔莫PH结构域依赖性调节对于Dock 180-埃尔莫复合物在吞噬作用和细胞迁移中起作用是必不可少的.使用埃尔莫及其同源物CED-12在秀丽隐杆线虫中进行的遗传拯救研究支持上述体内观察结果。这些数据揭示了PH结构域的一种新的作用模式和一种新的、进化上保守的机制，通过这种机制，一个二分的GEF可以激活Rac。
The members of the Dock180 superfamily of proteins are novel guanine nucleotide exchange factors (GEF) for Rho family GTPases and are linked to multiple biological processes from worms to mammals. ELMO is a critical regulator of Dock180, and the Dock180 - ELMO complex functions as a bipartite GEF for Rac. We identified a mechanism wherein the PH domain of ELMO, by binding the Dock180 - Rac complex in trans, stabilizes Rac in the nucleotide-free transition state. Mutagenesis studies reveal that this ELMO PH domain - dependent regulation is essential for the Dock180 - ELMO complex to function in phagocytosis and cell migration. Genetic rescue studies in Caenorhabditis elegans using ELMO and its homolog CED-12 support the above observations in vivo. These data reveal a new mode of action of PH domains and a novel, evolutionarily conserved mechanism by which a bipartite GEF can activate Rac.