Perelman School of Medicine at the University of Pennsylvania

Emeritus Professor of Physiology

Department of Physiology
B307 Richards Building
3700 Hamilton Walk
Philadelphia, PA 19104-6085

Phone: (215) 898-7017
Fax: (215) 573-5851

Other Perelman School of Medicine Affiliations
Cell and Molecular Biology Graduate Program
Program in Cellular Physiology

B.A., University of Pennsylvania, 1952
M.D., University of Pennsylvania, 1956

Research Description
My laboratory is studying the physiological regulation of the properties of the contractile proteins in cardiac muscle, with particular emphasis on the role of a myosin-binding protein in the modulation of the properties of the contraction.

In addition to myosin, the thick filament contains another protein that has been identified as myosin binding protein-C (MyBP-C). There are other myosin binding proteins, but MyBP-C is present in the largest amount, comprising 1-2 % of the myofibrillar mass. It is located along stripes in the region of the A band referred to as the C zone, each stripe separated by 43 nm from the adjacent ones. With this protein present in addition to myosin, it is possible to synthesize thick filaments with central bare zones, tapered ends and periodically distributed cross bridges arranged helically around the circumference of the filaments. Without this protein, the filaments are thicker, their lengths and thicknesses are very heterogeneous, clear central bare zones are not present, and myosin cross bridges may not be clearly discernible or ordered.

MyBP-C is present only in striated muscle, existing in 3 isoforms: two of the three isoforms are found only in skeletal muscle and the third only in the heart. Each skeletal MyBP-C contains 10 domains, consisting of 7 immunoglobulin C2 motifs and 3 fibronectin type III motifs arranged in the same order (identified as modules 1 to 10, N to C terminus). The cardiac isoform differs from the skeletal isoforms in three important ways (3): 1) cardiac MyBP-C contains an additional Ig module with 101 residues at the N terminus (module 0 or C0); 2) the 105 residue linker between the CI and C2 Ig domains (MyBP-C motif) contains 9 additional residues and 3 phosphorylation sites that are unique to the cardiac isoform; and 3) an additional 28 residues rich in proline are present in the C5 Ig domain. The skeletal isoforms are about 3 nm in diameter and 32 nm long, while the cardiac isoform is about 40-44 nm long because it contains an additional Ig domain (C0) at the N terminus and the MyBP-C motif.

MyBP-C has attracted greater attention since the demonstration that mutations in the gene produce about 40% of familial hypertrophic cardiomyopathy (FHC). Most of the mutations result in the lose of a critical binding site for myosin, but a mutation in the one region of MyBP-C can cause FHC without eliminating that site.

Completed work has already shown that phosphorylated MyBP-C stabilizes the structure of the thick filament by forming a collar around the thick filament. Interaction of the N terminus with actin promotes the formation of weak, non-force producing bonds between actin and myosin, leading to force generating, cycling cross bridges during Ca activation. Dephosphorylation of MyBP-C inhibits these functions. Current work is focused on determining the nature of the interactions of specific regions of MyBP-C that interact with actin and myosin and the way in which these interactions alter contractility. We are using small peptide sequences from MyBP-C that have been prepared by recombinant molecular biological methods to probe the function of specific regions of the whole MyBP-C molecule.


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