Krishnaswamy Laboratory

The Krishnaswamy Lab studies molecular mechanisms of blood coagulation. The lab investigates how the proteins of blood coagulation interact with each other and membranes to yield a regulated clotting response to vascular injury or an unregulated response in thrombotic or bleeding disease.

A regulated blood coagulation response to vascular injury is essential for life. Excessive bleeding is associated with a range of genetic or acquired conditions that impair the clotting response. Thrombotic diseases result from an exuberant or dysregulated clotting. Together, diseases associated with excessive clotting or bleeding represent one of the major causes of morbidity and mortality in the developed world.

Work in the Krishnaswamy Lab focuses on understanding the proteolytic activation steps in coagulation that are catalyzed by membrane assembled complexes assembled from the reversible binding of a serine protease to a protein cofactor on a membrane surface. A combination of biophysical, mutagenesis, and functional studies are used by the lab team to relate these binding steps to large increases in the function of the serine protease towards its biological substrate, and to understand how cofactors and membranes function in greatly enhancing the catalytic power of the enzyme complex.

The lab also studies how the biological substrate is recognized by the enzyme complex and the mechanisms by which substrate cleavage imparts biological activity in the product.

The Krishnaswamy Lab also uses x-ray crystallography, small angle x-ray scattering, single molecule reconstruction using high-resolution cryo-electron microscopy and hydrogen-deuterium exchange to provide structural insights into how the interactions between the components relate to function. The lab’s goal is to use mechanistic insights resulting from this work to reveal novel strategies to modulate the coagulation reactions for treatment of disease.