Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors
Multiple Factors Confer Specific Cdc42 and Rac Protein Activation by Dedicator of Cytokinesis (DOCK) Nucleotide Exchange Factors
复制标题
DOI：
10.1074/jbc.m111.236455
复制
发表时间：
2011-07-15
影响因子：
4.8
通讯作者：
Barford, David
中科院分区：
文献类型：
--
作者：
Kulkarni, Kiran;Yang, Jing;Barford, David
DOCK（胞质分裂专用因子）鸟嘌呤核苷酸交换因子（GEF）激活Rho家族GTP酶Rac和Cdc 42以控制细胞迁移、形态发生和吞噬作用。DOCK A和B亚家族激活Rac，而DOCK D亚家族激活Cdc 42。核苷酸交换由保守的DHR 2结构域（DOCKDHR 2）催化。虽然DOCKDHR 2介导的GTP酶激活的分子基础已通过DOCK 9（DHR 2）-Cdc 42复合物的结构阐明，但决定特异性GTP酶识别的因素尚不清楚。为了理解DOCK-GT β特异性的分子基础，我们已经确定了与Rac 1复合的DOCK 2（DHR 2）的晶体结构。DOCK 2（DHR 2）和DOCK 9（DHR 2）具有相似的三级结构和同源二聚体界面，并共享保守的GTP酶激活机制。DOCK 2（DHR 2）和DOCK 9（DHR 2）之间的多个结构差异解释了它们对Rac 1和Cdc 42的选择性。Cdc 42和Rac对其同源DOCK（DHR）2选择性的关键决定因素是β 3内的Phe或Trp残基（残基56）以及DOCK蛋白利用GEF诱导的开关1构象变化差异的能力，依赖于位置27处的不同残基。因此，DOCK蛋白与DH-PH GEF不同，DH-PH GEF通过识别β 2/β 3链内的结构差异来选择其同源GTP酶。
DOCK (dedicator of cytokinesis) guanine nucleotide exchange factors (GEFs) activate the Rho-family GTPases Rac and Cdc42 to control cell migration, morphogenesis, and phagocytosis. The DOCK A and B subfamilies activate Rac, whereas the DOCK D subfamily activates Cdc42. Nucleotide exchange is catalyzed by a conserved DHR2 domain (DOCKDHR2). Although the molecular basis for DOCKDHR2-mediated GTPase activation has been elucidated through structures of a DOCK9(DHR2)-Cdc42 complex, the factors determining recognition of specific GTPases are unknown. To understand the molecular basis for DOCK-GTPase specificity, we have determined the crystal structure of DOCK2(DHR2) in complex with Rac1. DOCK2(DHR2) and DOCK9(DHR2) exhibit similar tertiary structures and homodimer interfaces and share a conserved GTPase-activating mechanism. Multiple structural differences between DOCK2(DHR2) and DOCK9(DHR2) account for their selectivity toward Rac1 and Cdc42. Key determinants of selectivity of Cdc42 and Rac for their cognate DOCK(DHR)2 are a Phe or Trp residue within beta 3 (residue 56) and the ability of DOCK proteins to exploit differences in the GEF-induced conformational changes of switch 1 dependent on a divergent residue at position 27. DOCK proteins, therefore, differ from DH-PH GEFs that select their cognate GTPases through recognition of structural differences within the beta 2/beta 3 strands.