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Structure of an extended β3 integrin

Dongwen Zhou, Aye Myat Myat Thinn, Yan Zhao, Zhengli Wang and Jieqing Zhu

Key Points

  • Conformational extension is essential for integrin to fulfill its cell-adhesion function in platelet-mediated hemostasis and thrombosis.

  • High-resolution structures of β3 integrin in intermediate and extended conformations reveal atomic-level conformational rearrangements.

Abstract

Cells use adhesion receptor integrins to communicate with their surroundings. Integrin activation and cellular signaling are coupled with change from bent to extended conformation. β3 integrins, including αIIbβ3, which is essential for the function of platelets in hemostasis and thrombosis, and αVβ3, which plays multiple roles in diverse cell types, have been prototypes in understanding integrin structure and function. Despite extensive structural studies, a high-resolution integrin structure in an extended conformation remains to be determined. The human β3 Leu33Pro polymorphism, located at the PSI domain, defines human platelet-specific alloantigens 1a and 1b (HPA-1a/b), immune response to which is a cause of posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia. Leu33Pro substitution has also been suggested to be a risk factor for thrombosis. Here we report the crystal structure of the β3 headpiece in either Leu33 or Pro33 form, both of which reveal intermediate and fully extended conformations coexisting in 1 crystal. These were used to build high-resolution structures of full-length β3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how β3 integrin becomes extended at its β-knee region and how the flexibility of β-leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon β3 extension, which may affect the binding of conformation-dependent anti–HPA-1a alloantibodies. Our structural and functional data show that Leu33Pro substitution does not directly alter the conformation or ligand binding of β3 integrin.

  • Submitted January 26, 2018.
  • Accepted July 10, 2018.
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