This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Integrins are cell surface receptors that are important for development, wound healing, hemostasis, immunity and cancer. Functional integrins are typically non-covalent linked heterodimers of a and b subunits. Generally, integrins do not have intrinsic enzymatic ability and process signaling information into the cell through cytoplasmic adaptor molecules that recruit downstream effectors. Regulation of integrin activity is bidirectional in that in addition to extracellular ligand binding (outside-in signaling);intracellular queues (insideout signaling) can control integrin function. Despite its physiological importance, however, it is still unclear how these receptors process signaling information in the context of the full-length receptor. Activation of integrins needs to be coordinated and regulated or it may lead to diseased states, such as thrombotic disease and impairment of hemostasis. In the inactive state integrins have a compact structure with a diameter of ~140? and when activated extends to ~250-300?. To understand integrins'activation and regulation, we propose to use small angle X-ray scattering (SAXS) with detergent solubilized full-length integrins. The goals of this project are: 1) to determine the overall conformation of integrins in solution with buffer conditions that stabilize inactive or active conformations, and 2) characterize the conformational changes during the transition from inactive to active conformations. The expected results will be essential in the understanding of how integrins process signals bidirectionally through the membrane and provide important insights into the molecular mechasnisms underlying a wide assortment of hemostatic diseases, such as Glanzman's thrombasthenia.
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