Mechanisms of Integrin Receptor Transmembrane Signaling

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DESCRIPTION (provided by applicant): Our long-term research interest lies in striving to understand the structural basis of cell surface receptor transmembrane signaling and the concomitant relay of information to and from intracellular proteins. Particular focus is placed on the integrin family of cell-adhesion receptors, which is indispensable for the functioning of vertebrates and is of central importance to the operation of the vascular system. Integrins consist of two non-covalently associated subunits, termed alpha and beta, and possess the remarkable ability to transmit signals bidirectionally across the cell membrane. To do so, the single transmembrane helices of their two subunits must encode at least three functional states (inactive, inside-out and outside-in signaling). However, aside from recognizing that a separation of the transmembrane helices accompanies transmembrane signaling, little data, in particular structural data, is available about transmembrane helix packing, tilt and membrane embedding. In an effort to discover how an activating signal, following the binding of the cytoskeletal protein talin to the integrin beta cytosolic tail, is transmitted across the cell membrane, our research pursues the following specific aims: (i) Determination of the structure, dynamics and membrane embedding of the monomeric transmembrane helix of each integrin ?IIb and ?3 subunit. (ii) Elucidation of the structure, interaction and membrane embedding of the heterodimeric integrin ?IIb and ?3 transmembrane helices. (iii) Evaluation of the consequences of talin binding to the ?3 and ?IIb-??3 transmembrane structure, interaction and membrane embedding. We are using solution NMR spectroscopy to accomplish these goals. Peptides encompassing the integrin ?IIb-??3 transmembrane and cytosolic tails are produced recombinantly and they are reconstituted in lipid bilayer model membranes. Integrin ?IIb-??3 mediates blood platelet aggregation and, as such, is a key regulator of thrombosis. To effectively control and, if applicable, prevent thrombi, whose pathological appearances lead to heart attack and stroke, the molecular events leading to their formation must be understood. Thus, our research contributes to the understanding of the interactions of molecules and cells within the vascular system, and will aid in the development of drugs and therapies to treat vascular diseases. PUBLIC HEALTH RELEVANCE Stroke and heart attack, two of the major causes of death, arise from pathological aberrations of the vascular system. The current proposal provides the structural basis for understanding a key mediator of blot platelet aggregation and will aid in providing control of this process by drugs.