Faculty Collaboration Database

Structure of an extended β₃ integrin. Blood 2018 Aug 30;132(9):962-972

Date

07/19/2018

Pubmed ID

30018079

Pubmed Central ID

PMC6117741

DOI

10.1182/blood-2018-01-829572

Scopus ID

2-s2.0-85052783183 (requires institutional sign-in at Scopus site)   15 Citations

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 α_IIbβ₃, which is essential for the function of platelets in hemostasis and thrombosis, and α_Vβ₃, 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.

Author List

Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J

Author

Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Substitution
HEK293 Cells
Humans
Integrin beta3
Polymorphism, Genetic
Protein Domains
Protein Structure, Secondary
Structure-Activity Relationship