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Structure of an extended ?3 integrin.

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. ?3 integrins, including ?IIb?3, which is essential for the function of platelets in hemostasis and thrombosis, and ?V?3, 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 ?3 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 ?3 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 ?3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how ?3 integrin becomes extended at its ?-knee region and how the flexibility of ?-leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon ?3 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 ?3 integrin.

SUBMITTER: Zhou D

PROVIDER: S-EPMC6117741 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Structure of an extended β3 integrin.

Zhou Dongwen D Thinn Aye Myat Myat AMM Zhao Yan Y Wang Zhengli Z Zhu Jieqing J

Blood 20180717 9

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 stru ...[more]

PMID: 30018079

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Structure of an extended ?3 integrin.

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Structure of an extended β<sub>3</sub> integrin.

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Dataset Information

Structure of an extended ?3 integrin.

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Structure of an extended β&lt;sub&gt;3&lt;/sub&gt; integrin.

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Structure of an extended β<sub>3</sub> integrin.