Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation.
10.1007/s13238-012-2046-1
- Author:
Yan LIU
1
;
Yun ZHU
;
Sheng YE
;
Rongguang ZHANG
Author Information
1. National Laboratory of Biophysics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Crystallography, X-Ray;
Cytoskeletal Proteins;
chemistry;
metabolism;
Humans;
Integrins;
metabolism;
Membrane Proteins;
chemistry;
metabolism;
Mice;
Models, Molecular;
Muscle Proteins;
chemistry;
metabolism;
Neoplasm Proteins;
chemistry;
metabolism;
Protein Conformation
- From:
Protein & Cell
2012;3(6):434-440
- CountryChina
- Language:English
-
Abstract:
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.
