| Binding to collagens of extracellular proteins and cellular receptors is crucial for cell adhesion and signaling in hemostasis and immunity. We study the structure and function of von Willebrand factor (VWF) and leukocyte-associated Ig-like receptor-1 (LAIR-1) that respectively mediate the adhesion of blood platelets to collagen and the collagen-induced suppression of immune cell activity. Understanding the interactions that these proteins make to collagen is of potential therapeutic interest and may provide starting points for structure-based drug design. To further our insights in VWF and LAIR-1 interactions with collagen we will address the following questions: What is the structural basis of the VWF and LAIR-1 interaction with collagen? Are binding sites in single triple-helical collagen-peptides functionally equivalent to binding sites in fibrillar collagen? To answer the first question we will synthesize triple-helical collagen-peptides optimized for VWF and LAIR binding, study binding kinetics and resolve the three-dimensional protein-collagen structures by protein crystallography. To address the second question we will develop a recombinant expression system for the efficient production of mutant collagens in native fibrillar form, study binding kinetics and perform platelet and leukocyte adhesion studies. The anticipated results of the proposed research will advance substantially our understanding of specific collagen-protein interactions and will be of potential use for the development of therapies for human disease. |
