STRUCTURE, FUNCTION & MECHANISM OF CONTRACTILE PROTEINS

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The Program Project (Pennsylvania Muscle Institute) functions as in interdisciplinary program for collaborative studies on the molecular mechanism of muscle contraction and myosin-based cell motility. The major themes of the Program are the structural biology, mechano-chemistry, protein design and sequence specificity of the contractile proteins. It integrates investigations from genetic expression, isoform diversity, enzymatic activity, molecular motions and reaction kinetics in isolated contractile protein molecules fully constituted myofibrils. The objective is to understand how these proteins, individually and organized in highly specific, macromolecular assemblies, perform their task of chemical, structural and mechanical energy transduction at the molecular level. The projects and investigators within the Program are interdependent and closely linked through complementary research goals and shared technologies, resources and training programs. Novel instrumentation to be developed for the research will include laser optical traps, determination of force, translocation distance and inter-domain motions of both single molecules and ordered arrays of contractile proteins, time-resolved fluorescence polarization microscopy, and ultra-rapid freezing electron microscopy synchronized to transient molecular events. These transients will be initiated by laser pulse photolysis of "caged" substrate or signaling molecules and by rapid mechanical perturbations. Novel techniques will include new eukaryotic co-expression systems for protein structure-function studies, transgenic expression of truncated, mutated or chimeric proteins in genetically amenable organisms, bifunctional fluorescence labeling for quantitative protein orientational dynamics and mechanical analysis of single myofibrils. Myosin from specialized tissues, such as smooth and oscillatory muscles, will be studied intensively. The long-term scientific aims and technologies developed in the Program Project are directed to understanding the normal assembly and function as well as pathophysiology of contractile proteins relevant to the cardiovascular and pulmonary systems.