Sivaraj Sivaramakrishnan
Sivaraj Sivaramakrishnan
Assistant Professor
sivaraj@umich.edu

Research Description

Emergent behavior of multiple molecular motors; Protein engineering of FRET bio-sensors; Signaling pathways in cardiac hypertrophy Research Topics The laboratory research spans the fields of single molecule biophysics, protein biochemistry and cell biology and integrates a variety of experimental and computational approaches. Coordinated function of the myosin family of molecular motors Myosins are actin-based molecular motors implicated in diverse cellular processes. They are cellular engines that convert the chemical energy derived from the hydrolysis of ATP to mechanical motion. A lot is known about the structure and function of myosin molecules and the interaction of single myosins with single actin filaments. Myosin function in vivo is an emergent property of the simultaneous interaction of multiple myosins with multiple actin filaments. These coordinated interactions are essential for cellular processes such as membrane trafficking, mRNA transport and maintenance of membrane tension. An unexplored frontier in molecular motor research is how the same motor interacts with different subcellular compartments to perform different cellular functions. The laboratory uses a model experimental system (Figure 1), developed by Dr. Sivaramakrishnan, to examine the movement of organelle-sized nanostructures linked to different numbers and types of myosin motors on an organized meshwork of actin filaments. Regulation of protein-protein interaction using an ER/K α-helix Cell biological processes in health and disease are regulated by dynamic interactions between proteins. We use a technique termed SPASM (Systematic Protein Affinity Strength Modulation) to regulate the strength of protein-protein interactions in vivo. SPASM involves two interacting proteins separated by an ER/K helix of designed mechanical stiffness. The ER/K helix acts as a semi-flexible structure that regulates the strength of interaction between the proteins it separates. The mechanical properties of the helix can be engineered systematically to alter the affinity of the protein-protein interaction. The laboratory is focused on the use of SPASM for a variety of applications including the design of FRET bio-sensors, protein concentration sensors (Figure 2) and modulating autoinhibition of enzymes such as kinases. Contractility and signaling in cardiomyocytes Cardiomyocytes have a highly organized acto-myosin cytoskeleton that drives contractility of heart muscle. Contractility of cardiomyocytes is influenced by numerous factors including the control of sarcomeric proteins by calcium signaling. Genetic mutations in sarcomeric proteins such as β-cardiac myosin can also influence contractility in diseases such as β-cardiac myosin. Recent technological advances have enabled the contractility measurements of isolated cardiomyocytes under physiological load conditions (Figure 3). The laboratory is broadly interested in the development of FRET bio-sensors to act as spatio-temporal probes of signaling events in cardiomyocytes during normal and disease states.

Education

Postdoctoral Fellowship Stanford University
Ph.D. Northwestern University
M.S. University of Illinois, Urbana-Champaign
B.S. University of Pune, India