Protein-protein interaction in intracellular signal transduction

Vav是Rho/Rac家族的鸟嘌呤核苷酸交换因子，仅在造血细胞中表达。生长因子受体结合蛋白2 （Grb2）通过Vav的c端Srchomology 3 （SH3）结构域（GrbS）和n端SH3结构域（VavS）的二聚化，在Vav的膜定位和激活中发挥重要作用。求解了VavS与GrbS络合的晶体结构。VavS与其他SH3结构域蛋白的不同之处在于，其富含脯氨酸肽的结合位点被自身的RT环阻断。VavS β筒的一端形成一个凹的疏水表面。GrbS组件与VavS表面形成一个连续的互补接口。GrbS对VavS的结合位点与富含脯氨酸肽的典型结合位点部分重叠，但绝对不同。界面突变导致VavS对GrbS的结合亲和力降低4- 40倍。该结构揭示了GrbS如何在不与富含脯氨酸基序结合的情况下特异性地将VavS与其他信号分子区分开来。

Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is expressed exclusively in hematopoietic cells. Growth factor receptor-bound protein 2 (Grb2) has been proposed to play important roles in the membrane localization and activation of Vav through dimerization of its C-terminal Srchomology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav (VavS). The crystal strucuture of VavS complexed with GrbS has been solved. VavS is distinct from other SH3 domain proteins in that its binding site for proline-rich peptides is blocked by its own RT loop. One of the ends of the VavS β-barrel forms a concave hydrophobic surface. The GrbS components make a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site for proline-rich peptides, but is definitely different. Mutations at the interface caused a decrease in the binding affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS discriminates VavS specifically from other signaling molecules without binding to the proline-rich motif.