This program brings together investigators with expertise on the function and structure of cell surface glycoproteins, and focuses their effects on integrins and related molecules that are of great importance in the normal function of the vasculature, and in vascular disease. Integrins are highly sophisticated cell surface molecules that link the extracellular environment to the interior of the cell. A three-dimensional structure is essential for further progress in the integrin field. Integrins, like other vascular cell surface glycoproteins can help illuminate the structural biology of integrins. Other vascular proteins are functionally related to integrins; selectins and integrins both function in leukocyte localization in inflammation, and both selectins and some integrins can mediate leukocyte rolling. Project investigates the molecular and biophysical basis in leukocyte rolling through selectins, alpha4 integrins, MadCAM-1, and VCAM-1. Shear-enhanced bond formation; the kinetics and mechanical properties of alpha4 integrin interactions with IgSF members; the function of mucin-like domains and microvillous tethers; prevention of selectin uprooting by transmembrane and cytoplasmic domains; and the structural basis for Ca2+-dependent rolling through alpha4 integrins is investigated. The next two projects involve a close collaboration to understand the structural basis of integrin function, with the majority of protein production in Dr. Springer's and the majority of structure determination . Dr. Wang's project Crystal structures will be determined of beta2 integrins, ICAMs, and the complexes and fragments. As alternative integrins, alpha2beta1, alphaIIbbeta3, and alpha6beta4 are examined. As alternatives to intact integrin ectodomains, structures will be determined for truncated alphabeta heterodimers, modular fragments of the alpha and beta subunits, and surrogate proteins with sequence homology to integrins. The function of modular units is examined in ligand binding and signaling. As related structural modules, beta- propellar domains with YWTD or related motifs are investigated in a fragment of nidogen bound to laminin, and in an archaebacterial surface layer protein and M. tuberculosis Ser/Thr kinase. The last project uses module dissection, NMR, and crystallography to provide a structural basis for understanding the functions of the integrin EGF-like modules that form the stalks of integrin-beta-subunits; and the YWTD beta- propeller and flanking EGF modules in the low-density lipoprotein receptor that are homologous to similar modules in nidogen and the epidermal growth factor (EGF) precursor. The last project provides support for obtaining crystal quality proteins.
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