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Structure and function of myosin binding protein C

MyBP-C is a myosin binding protein discovered in the 1970s whose structural organization and function have remained elusive. It is currently a topical area of research because of its role in regulating cardiac contraction and because mutations in MyBP-C cause are a major cause of heart (and skeletal muscle) disease. We collaborated with Dr. Pradeep Luther (Imperial College, London) who carried out electron tomography of especially well (cryo) preserved muscle specimens prepared in our lab. The tomograms show that MyBP-C is not only bound to the thick filament, but also extends out and connects to the thin filaments (the pink band of density in the figure; Luther et al., PNAS 2011). This was the first demonstration that interactions of MyBP-C with actin observed in vitro may be relevant to intact muscle. Bridging between myosin and actin provides a physical basis for MyBP-C’s ability to modulate contraction. We are now pursuing further aspects of MyBP-C structure and function by cryo-EM, in collaboration with Drs. David Warshaw at University of Vermont and Richard Moss at University of Wisconsin.

Craig Lab - UMMS - MyBPC thick filament

In vitro motility studies show that the binding of cardiac MyBP-C to thin filaments affects their regulation by Ca2+, causing activation in the absence of Ca2+. Could MyBP-C alter the position of tropomyosin on actin so that the myosin binding site becomes exposed? We have investigated this question by negative staining and 3D image reconstruction, in collaboration with Drs. Michael Previs and David Warshaw at University of Vermont. As discussed in Actin filament structure, Ca2+ causes activation by displacement of tropomyosin from its myosin-blocking position (A, below) to a non-blocking position (B, C). When N-terminal domains of MyBP-C bind to thin filaments in the absence of Ca2+, we find that tropomyosin is displaced to the high Ca2+ position, providing a direct explanation of the thin filament activation observed in vitro. These results provide structural insights into MyBP-C’s ability to modulate contraction in vivo (Mun et al., 2014). We are currently using EM and image reconstruction to determine whether similar effects occur with skeletal MyBP-C, whose function is less well understood than cardiac.

Craig Lab - UMMS - MyBPC thin filament