PH domain of ELMO functions in trans to regulate Rac activation via Dock180

被引：103

作者：

Lu, MJ

Kinchen, JM

Rossman, KL

Grimsley, C

deBakker, C

Brugnera, E

Tosello-Trampont, AC

Haney, LB

Klingele, D

Sondek, J

Hengartner, MO

Ravichandran, KS ^{[1
]}

机构：

[1] Univ Virginia, Dept Microbiol, Beirne Carter Ctr Immunol Res, Charlottesville, VA 22908 USA

[2] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

[3] Univ Zurich, Inst Mol Biol, CH-8057 Zurich, Switzerland

[4] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA

[5] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2004年 / 11卷 / 08期

关键词：

D O I：

10.1038/nsmb800

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：756 / 762

页数：7

共 32 条

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