Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation
Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation
复制标题
DOI：
10.1016/s0092-8674(00)00085-4
复制
发表时间：
2000-09-01
期刊：
影响因子：
64.5
通讯作者：
Rosen, MK
中科院分区：
文献类型：
--
作者：
Aghazadeh, B;Lowry, WE;Rosen, MK
rho家族gtp酶转导来自受体的信号，导致细胞形状和运动、有丝分裂和发育的变化。含有Dbl同源（DH）结构域的蛋白质通过催化GDP交换GTP来激活Rho GTPase，受体启动的Dbl蛋白Vav交换活性刺激涉及酪氨酸磷酸化，我们通过结构测定发现mVav1 DH结构域被位于GTPase相互作用位点的n端延伸自抑制。该延伸包含Tyr174 src家族激酶识别位点，该肽的磷酸化或截断导致GEF活性的刺激。核磁共振波谱数据表明，n端肽被从DH结构域释放出来，磷酸化后变得非结构化。因此，酪氨酸磷酸化通过暴露DH结构域的GTPase相互作用表面来缓解自身抑制，这是Vav激活所必需的。
Rho-family GTPases transduce signals from receptors leading to changes in cell shape and motility, mitogenesis, and development. Proteins containing the Dbl homology (DH) domain are responsible for activating Rho GTPases by catalyzing the exchange of GDP for GTP, Receptor-initiated stimulation of Dbl protein Vav exchange activity involves tyrosine phosphorylation, We show through structure determination that the mVav1 DH domain is autoinhibited by an N-terminal extension, which lies in the GTPase interaction site. This extension contains the Tyr174 Src-family kinase recognition site, and phosphorylation or truncation of this peptide results in stimulation of GEF activity. NMR spectroscopy data show that the N-terminal peptide is released from the DH domain and becomes unstructured upon phosphorylation. Thus, tyrosine phosphorylation relieves autoinhibition by exposing the GTPase interaction surface of the DH domain, which is obligatory for Vav activation.