1) ADHESIVE MOLECULAR INTERACTIONS IN PLATELET FUNCTION; 2) BACTERIAL SIGNALING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (i) The interactions between the A1 domain of von Willebrand factor(VWF) and the platelet membrane receptor glycoprotein (GP) Ibalpha plays a crucial role in the arrest of bleeding where blood flow is rapid and also in the pathological thrombus formation leading to arterial occlusion. Additionally, GP Ibalpha interacts with thrombin which in turn activates platelets and regulates blood clotting. Both these interactions are mediated through the N-terminal domain of the glycoprotein (GP IbalphaN). The goal of this proposal is to study the interactions of GPIbalphaN with thrombin and vWF A1 and thrombin by crystallographic techniques. Mutations in VWF A1 and GPIbalphaN cause bleeding disorders. We are investigating the effects of these mutations on inter-molecular interactions by analyzing the crystal structures of the complexes. (ii) Bacteria use the two-component systems to adapt to changes in the environmental conditions. In response to deteriorating conditions of growth, certain types of bacteria form spores in order to preserve the genetic material until growth conditions turn favorable again. The formation of spores in Bacillus subtilis is controlled by an expanded version of the two-component system called the phosphorelay. We are carrying out crystallographic studies aimed at elucidating the mechanism of phosphorelay signaling at the molecular level.