A New Model of Cooperative Myosin-Thin Filament Binding

Abstract

Cooperative myosin binding to the thin filament is critical to regulation of cardiac and skeletal muscle contraction. This report delineates and fits to experimental data a new model of this process, in which specific tropomyosin-actin interactions are important, the tropomyosin-tropomyosin polymer is continuous rather than disjointed, and tropomyosin affects myosin-actin binding by shifting among three positions as in recent structural studies. A myosin- and tropomyosin-induced conformational change in actin is proposed, rationalizing the approximately 10,000-fold strengthening effect of myosin on tropomyosin-actin binding. Also, myosin S1 binding to regulated filaments containing mutant tropomyosins with internal deletions exhibited exaggerated cooperativity, implying an allosteric effect of tropomyosin on actin and allowing the effect's measurement. Comparisons among the mutants suggest the change in actin is promoted much more strongly by the middle of tropomyosin than by its ends. Regardless of calcium binding to troponin, this change in actin facilitates the shift in tropomyosin position to the actin inner domain, which is required for tight myosin-actin association. It also increases myosin-actin affinity 7-fold compared with the absence of troponin-tropomyosin. Finally, initiation of a shift in tropomyosin position is 100-fold more difficult than is its extension from one actin to the next, producing the myosin binding cooperativity that underlies cooperative activation of muscle contraction.

Designing Heart Performance by Gene Transfer

“…Tropomyosin can exist as either a homo-or heterodimer in the adult heart (␣␣, ␣␤, or ␤␤ but is mostly limited to ␣␣ homodimers). Tropomyosin has been the subject of a range of structure-function studies that utilized elegant biochemical methodologies (282,283,353,360,362,550,888,889). A better understanding of Tm's role under both physiological and pathophysiological conditions in intact cardiac myocytes has been gained through the use of gene transfer technology.…”

The Δ14 Mutation of Human Cardiac Troponin T Enhances ATPase Activity and Alters the Cooperative Binding of S1-ADP to Regulated Actin

“…The method used was similar to that of Tobacman and Butters (38). Measurements were made in a Spex Fluorolog fluorescence spectrophotometer at 25 °C with 0.5 mm slits, excitation at 364 nm, and emission at 384 nm.…”

Mechanistic Heterogeneity in Contractile Properties of α-Tropomyosin (TPM1) Mutants Associated with Inherited Cardiomyopathies

“…The RTF is composed of F-actin, Tm, and the Tn complex and responds to Ca 2ϩ with a series of conformational changes. The most widely accepted model linking Ca 2ϩ and muscle contraction is the three-state model (9,10). In the absence of Ca 2ϩ , Tm physically occludes the myosin-binding sites on actin to produce the blocked state.…”