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Actin filament structure

The thin (actin) filaments that the myosin motors pull on to cause shortening also contain the proteins tropomyosin and troponin, which regulate contraction. Our goal is to understand the structural basis of this regulation. In work with Dr. Bill Lehman (Boston University School of Medicine), 3D reconstruction of negatively stained thin filaments (first image) demonstrated that the elongated tropomyosin molecule (red strand in second image) blocks the binding of myosin heads to the thin filament in the low Ca2+ (off-) state by obscuring the myosin binding site on actin.  When the thin filament is activated by Ca2+ binding to troponin, tropomyosin moves to partially unblock this site (yellow strand), allowing myosin to bind. When myosin binds, it pushes tropomyosin further (green strand), fully opening the myosin binding site.  These results directly revealed the mechanism of the “steric-blocking” model of regulation, which had previously been postulated based on X-ray diffraction of muscle.  Current studies are directed at obtaining a molecular model of the thin filament including actin, tropomyosin and troponin by high-resolution cryo-EM (third image). We so far have a 5 Å map of F-actin, demonstrating feasibility (fourth image, showing α-helices in actin subunits).

Roger Craig Lab - UMMS - thin filament cryo