Protein-protein interaction in intracellular signal transduction

Vav是Rho/Rac家族的一种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)通过二聚化Vav的C端SH3(SH3)结构域(GRBS)和N端SH3结构域(VAVS)，在Vav的膜定位和激活中发挥重要作用。解决了VAVS与GRBs络合的晶体结构问题。VAVS与其他SH3结构域蛋白的不同之处在于，它与富含Pro的多肽的结合位置被它自己的RT环所阻断。VAVSβ-Barrel的一端形成了凹陷的疏水表面。伽玛暴组件与VAVS表面形成连续的互补界面。GRB与VAVS的结合部位与富含Pro的多肽的典型结合部位部分重叠，但明显不同。界面突变导致VAVS与伽玛暴的结合亲和力下降4-40倍。该结构揭示了GRB如何在不与富含脯氨酸的基序结合的情况下，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.