This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Integrins are a family of transmembrane receptors that regulate cell migration, differentiation, programmed cell death, and cell adhesion. Specifically, the human integrin alpha-11-beta-3 regulates platelet aggregation, which can lead to thrombus formation in a coronary artery following the rupture of an atherosclerotic plaque and ultimately myocardial infarction. The various functions of integrin molecules are controlled by dynamic linkages between extracellular adhesion molecules and the intracellular environment, which are in turn regulated by transmembrane signaling resulting from the binding of extracellular ligands and molecules to the cytoplasmic domain. Dr. Yeagers laboratory has previously utilized electron cryo-microscopy to determine the structure of full-length alpha-11-beta-3 in the low-affinity, inactive conformation, which along with X-ray crystallographic studies enabled a model to be proposed for the structural rearrangements associated with integrin activation. We wish to test this model by utilizing electron cryo-microscopy to improve the resolution of the 3D reconstruction of alpha-11-beta-3 in the low-affinity state and to generate a 3D map of the high-affinity state in the presence of bound ligands. These studies should provide crucial insight into the molecular basis of integrin activation, which will be relevant for the design of novel therapeutic agents.
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