Volume 3 Issue 6
Jun.  2012
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Yan Liu, Yun Zhu, Sheng Ye, Rongguang Zhang. Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation[J]. Protein&Cell, 2012, 3(6): 434-440. doi: 10.1007/s13238-012-2046-1
Citation: Yan Liu, Yun Zhu, Sheng Ye, Rongguang Zhang. Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation[J]. Protein&Cell, 2012, 3(6): 434-440. doi: 10.1007/s13238-012-2046-1

Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation

doi: 10.1007/s13238-012-2046-1
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We thank Prof. Jun Qin (Cleveland Clinic, OH, USA) for his valuable comments and critical discussion. We also thank Ms. Ping Shan in our laboratory for her kindly help during this study. We are very grateful to the staff of the Structural Biology Core Facility in the Institute of Biophysics, Chinese Academy of Sciences, for their technical assistance, especially to Ms. Ya Wang and Mr. Yi Han. This work was supported by the 973 Program of the Ministry of Science and Technology of China (Grant Nos. 2011CB911101 and 2012CB910304).

  • Received Date: 2012-05-14
  • Rev Recd Date: 2012-05-24
  • 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.
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