The central theme of this project is to define the functional diversity among members of the integrin family of cell adhesion receptors. The receptors in the integrin subfamilies (Beta1-Beta5) regulate diverse biological processes, including thrombosis and the immune surveillance via their recognition of specific ligands. The integrin receptors share gross structural features and possess a high degree of sequence identity among their alpha and Beta subunits, particularly among the Beta subunits. Many receptors within the subfamilies execute adhesive function by binding ligand through Arg-Gly-Asp (RGD) sequences. On platelet GPIIb-IIIa, the RGD peptides are crosslinked to a site within residues 109-171 of GPIIIa, a region remarkably conserved among integrin Beta subunits, thereby suggesting a functional involvement for residues 109-171 in binding RGD containing ligands. alpha5Beta1 is the prototypic fibronectin receptor which binds its ligand through RGD sequences, and alpha 2 Beta, may interact with collagen through an RGD recognition. Studies involving chemical crosslinking, proteolytic fragmentation, immunochemical mapping, and NH2-terminal sequencing will be utilized to localize the RGD binding sites within the subunits of Beta1. The goals will be to determine if the homologous region of Beta3 (residues 109-171) is involved in RGD binding and crosslinking to the Beta1 subfamily. Recently a distinct non-RGD region of fibronectin was shown to mediate binding of this ligand to alpha4Beta1 from the Beta1 subfamily. Therefore in parallel, the hypothesis will be tested that distinct region(s) in alpha4Beta1 of the Beta1 subfamily is involved in non-RGD recognition. The primary function of regions within RGD and non-RGD crosslinking domains of these Beta, integrins will be assessed by testing synthetic peptides and site-specific anti-peptide antibodies for their capacity to inhibit specific adhesive functions dependent upon members of Beta1 subfamily. Ultimately, key functional reagents will be identified to define the basic structure- function relationships within the integrins. These reagents and molecular insights should yield fundamental information on how integrins recognize their ligands and provide to many diseases new approaches to manipulating elected integrin function.
| Bartoli, Carlo R; Dassanayaka, Sujith; Brittian, Kenneth R et al. (2014) Insights into the mechanism(s) of von Willebrand factor degradation during mechanical circulatory support. J Thorac Cardiovasc Surg 147:1634-43 |
