The image to the left is rendered from an ensemble of solution NMR structures of magnesium loaded cardiac troponin C bound to cardiac troponin I. These structures represent the possible dynamic alterations in troponin C, the calcium signal present during the resting state of cardiac muscle contraction.
Bacterial Virulence Factors
Bacterial pathogens have numerous strategies for causing diseases in humans and animals. Microbes make proteins known as toxins that facilitate attachment to the host and disruption of normal cell functions. Inhibiting these toxins impairs the microbe's ability to infect cells. We are studying how bacterial toxins are activated and applying this information to the development of new therapeutics.
The rate and force of muscle contraction are controlled through the interaction of sarcomeric proteins. Dysregulation of contraction leads to several muscle diseases. We utilize biophysical and biochemical approaches to examine the structure and dynamics of skeletal and cardiac muscle regulatory proteins. The long term goal is to design better diagnostics and treatments for heart failure and skeletal muscle disorders.
According to the American Heart Association, heart failure (HF) is one of the most significant causes for hospital visits in Western countries. Considerable interest exists in determining the molecular mechanisms controlling contractility and how modification of this process leads to cardiac dysfunction and HF. Many mutations linked to hypertrophic cardiomyopathy (HC) and HF are located in the gene encoding for cardiac myosin binding protein C (cMyBP-C).A modular protein by design, cMyBP-C is composed of domains C0-C10, which participate in the control of contractility and organization of the thick filament. Mutations in cMyBP-C alter sarcomeric structure and induce contractile disorders by unknown molecular mechanisms. The long term goal of my laboratory is to understand cMyBP-C’s structural and regulatory roles in normal and dysfunctional cardiac muscle contraction. Improved structural understanding of cMyBP-C will potentiate the development of novel diagnostic and therapeutic strategies to treat HC and HF. To this end, we employ computational, biochemical, biophysical, and solution NMR approaches to investigate the structural mechanisms controlling cMyBP-C association with thick filament proteins.
