%A Yan Liu, Yun Zhu, Sheng Ye, Rongguang Zhang %T Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation %0 Journal Article %D 2012 %J Protein Cell %J Protein & Cell %@ 1674-800X %R 10.1007/s13238-012-2046-1 %P 434-440 %V 3 %N 6 %U {https://journal.hep.com.cn/pac/EN/10.1007/s13238-012-2046-1 %8 2012-06-01 %X

Kindlin-2 belongs to a subfamily of FERM domain containing proteins, which plays key roles in activating integrin transmembrane receptors and mediating cell adhesion. Compared to conventional FERM domains, kindlin-2 FERM contains an inserted pleckstrin homology (PH) domain that specifically binds to phosphatidylinositol (3,4,5) trisphosphate (PIP3) and regulates the kindlin-2 function. We have determined the crystal structure of kindlin-2 PH domain at 1.9 ? resolution, which reveals a conserved PH domain fold with a highly charged and open binding pocket for PIP3 head group. Structural comparison with a previously reported solution structure of kindlin-2 PH domain bound to PIP3 head group reveals that upon PIP3 insertion, there is a significant conformational change of both the highly positively charged loop at the entry of the PIP3 binding pocket and the entire β barrel of the PH domain. We propose that such “induced-fit” type change is crucial for the tight binding of PIP3 to anchor kindlin-2 onto the membrane surface, thereby promoting its binding to integrins. Our results provide important structural insight into kindlin-2-mediated membrane anchoring and integrin activation.