Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation.
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 Å 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.
National Laboratory of Biophysics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Yan
Y
Liu
Yun
Y
Zhu
Sheng
S
Ye
Rongguang
R
Zhang
D000818:Animals; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
D003598:Cytoskeletal Proteins; C477322:FERMT3 protein, human; D016023:Integrins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; C527802:kindlin-2 protein, mouse