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Biomedical subjects

Saul Winegrad

Publications and source records attributed to Saul Winegrad.

4 recordsLinked to original sources
PubMed2005

Myosin-binding protein C phosphorylation, myofibril structure, and contractile function during low-flow ischemia.

BACKGROUND: Contractile dysfunction develops in the chronically instrumented canine myocardium after bouts of low-flow ischemia and persists after reperfusion. The objective of this study is to identify whether changes in the phosphorylation state of myosin-binding protein C (MyBP-C) are a potential cause of dysfunction. METHODS AND RESULTS: During low-flow ischemia, MyBP-C is dephosphorylated, and the number of actomyosin cross-bridges in the central core of the sarcomere decreases as thick filaments dissemble from the periphery of the myofibril. During reperfusion, MyBP-C remains dephosphorylated, and its degradation is accelerated. CONCLUSIONS: Dephosphorylation of MyBP-C may initiate changes in myofibril thick filament structure that decrease the interaction of myosin heads with actin thin filaments. Limiting the formation of actomyosin cross-bridges may contribute to the contractile dysfunction that is apparent after low-flow ischemia. Breakdown of MyBP-C during reperfusion may prolong myocardial stunning.

Actins↗
PubMed2003

Myosin-binding protein C (MyBP-C) in cardiac muscle and contractility.

Both the MyBP-C motif between C1 and C2 and the C5 module are important regions for implementing the effect of MyBP-C on myosin and on contractility but in different ways. C5 may determine the folding of MyBP-C and the manner in which MyBP-C interacts with myosin. In spite of its apparent importance this interaction does not appear to be physiologically regulated. Its alteration by mutation however can have a major effect on contractility. On the other hand, the effect of the motif is regulated by phosphorylation and appears to be an important part of a physiological mechanism(s) for modulating contractility. Thick filaments isolated from cardiac muscle exist in one of three different structures (Levine et al 2001). Different degrees of phosphorylation of MyBP-C can produce transitions among the three structures. The combination of the binding results of Flashman et al (2002) with the data of McClellan et al (2001) suggests that the C5 interaction with C8 is critical in maintaining the normal structure of thick filaments and the normal function of the force generators in the filaments. The cardiac-specific sequence in C5 and its normal interaction with another part of the same or a different MyBP-C may be required for the correct 3 dimensional shape of the three MyBP-C molecules at each locus in the C zone and the normal structure of the thick filament. The normal interactions may be necessary to allow transitions in binding and filament structure that are associated with phosphorylation of the MyBP-C motif.

Amino Acid Motifs↗
PubMed2003

Effect of MyBP-C binding to actin on contractility in heart muscle.

In contrast to skeletal muscle isoforms of myosin binding protein C (MyBP-C), the cardiac isoform has 11 rather than 10 fibronectin or Ig modules (modules are identified as C0 to C10, NH2 to COOH terminus), 3 phosphorylation sites between modules C1 and C2, and 28 additional amino acids rich in proline in C5. Phosphorylation between C1 and C2 increases maximum Ca-activated force (Fmax), alters thick filament structure, and increases the probability of myosin heads on the thick filament binding to actin on the thin filament. Unphosphorylated C1C2 fragment binds to myosin, but phosphorylation inhibits the binding. MyBP-C also binds to actin. Using two types of immunoprecipitation and cosedimentation, we show that fragments of MyBP-C containing C0 bind to actin. In low concentrations C0-containing fragments bind to skinned fibers when the NH2 terminus of endogenous MyBP-C is bound to myosin, but not when MyBP-C is bound to actin. C1C2 fragments bind to skinned fibers when endogenous MyBP-C is bound to actin but not to myosin. Disruption of interactions of endogenous C0 with a high concentration of added C0C2 fragments produces the same effect on contractility as extraction of MyBP-C, namely decrease in Fmax and increase in Ca sensitivity. These results suggest that cardiac contractility can be regulated by shifting the binding of the NH2 terminus of MyBP-C between actin and myosin. This mechanism may have an effect on diastolic filling of the heart.

Actins↗