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
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.
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
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.
is present only in striated muscle, existing in 3 isoforms:
two of the three isoforms are found only in
muscle and the third only in the heart. Each skeletal
MyBP-C contains 10 domains, consisting of 7 immunoglobulin
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
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)
28 residues rich in proline are present in the C5 Ig
domain. The skeletal isoforms are about 3 nm in diameter
nm long, while the cardiac isoform is about 40-44 nm
it contains an additional Ig domain (C0) at the N terminus
and the MyBP-C motif.
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.
work has already shown that phosphorylated MyBP-C stabilizes
structure of the thick filament
a collar around the thick filament. Interaction of
the N terminus with actin promotes the formation
non-force producing bonds between actin and myosin,
leading to force
generating, cycling cross bridges during Ca activation.
of MyBP-C inhibits these functions. Current work
is focused on determining the nature of the interactions
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
been prepared by recombinant molecular biological
methods to probe the function of specific regions of
Winegrad. Myosin binding protein C, a potential regulator
of cardiac contractility. Circ. Res. 2000; 86:6
Winegrad. How actin-myosin interactions differ with different
of myosin. Circ. Res. 1999; 82: 1109-1110.
Winegrad. Cardiac myosin binding protein C. Circ. Res.
Winegrad, D. Henrion, L. Rappaport, J-L. Samuel. Self-protection
of cardiac myocytes from hypoxia
Res. 1999; 85: 690-698.
B.Millman, I.Kulikovskaya, G.McClellan & S.Winegrad.
Multiple Structures of Thick Filaments in Resting
Cardiac Muscle and their Influence on Cross Bridge
Interactions. Biophys. J. 2001; 81: 1070-1082.
McClellan, I. Kulikovskaya, S. Winegrad. Changes
in Cardiac Contractility Related to Calcium Mediated
in Phosphorylation of Myosin Binding Protein-C.
Biophys. J. 2001; 81: 1083-1092.
Winegrad. Gene Mutation in Cardiac Myosin Binding Protein
Molec. Cell. Cardiol..
Kulikovskaya, G. McClellan, R. Levine, and S. Winegrad.
Effect of extraction of myosin
binding protein C on
contractility of rat heart. Amer.J. Physiol
2003; 285: H857-H865.
Kulikovskaya, G. McClellan, J. Flavigny, L. Carrier and
S. Winegrad Effect
on Contractility in Heart Muscle J. Gen.
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a full list of publications
(searches the National Library of Medicine's PubMed database.)