Structural Basis of Membrane Targeting by the Dock180 Family of Rho Family Guanine Exchange Factors (Rho-GEFs)

被引:50
|
作者
Premkumar, Lakshmanane
Bobkov, Andrey A. [2 ]
Patel, Manishha [3 ]
Jaroszewski, Lukasz [2 ]
Bankston, Laurie A.
Stec, Boguslaw [1 ]
Vuori, Kristiina [2 ]
Cote, Jean-Francois [3 ]
Liddington, Robert C. [1 ]
机构
[1] Sanford Burnham Med Res Inst, Infect & Inflammatory Dis Ctr, La Jolla, CA 92037 USA
[2] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA
[3] Univ Montreal, Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada
基金
美国国家卫生研究院;
关键词
X-RAY-DIFFRACTION; NUCLEOTIDE-EXCHANGE; C2; DOMAIN; CELL-MIGRATION; MYOBLAST CITY; CRKII/DOCK180/RAC PATHWAY; APOPTOTIC CELLS; CDC42; ACTIVATOR; BINDING; PROTEIN;
D O I
10.1074/jbc.M110.102517
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 Dock180 family of atypical Rho family guanine nucleotide exchange factors (Rho-GEFs) regulate a variety of processes involving cellular or subcellular polarization, including cell migration and phagocytosis. Each contains a Dock homology region-1 (DHR-1) domain that is required to localize its GEF activity to a specific membrane compartment where levels of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P-3) are up-regulated by the local activity of PtdIns 3-kinase. Here we define the structural and energetic bases of phosphoinositide specificity by the DHR-1 domain of Dock1 (a GEF for Rac1), and show that DHR-1 utilizes a C2 domain scaffold and surface loops to create a basic pocket on its upper surface for recognition of the PtdIns(3,4,5)P-3 head group. The pocket has many of the characteristics of those observed in pleckstrin homology domains. We show that point mutations in the pocket that abolish phospholipid binding in vitro ablate the ability of Dock1 to induce cell polarization, and propose a model that brings together recent mechanistic and structural studies to rationalize the central role of DHR-1 in dynamic membrane targeting of the Rho-GEF activity of Dock180.
引用
收藏
页码:13211 / 13222
页数:12
相关论文
empty
未找到相关数据