Persistence Length of Human Cardiac α-Tropomyosin Implies Near-Neighbor Cooperative Activation of Cardiac Thin Filaments

Abstract

Indirect flight muscle (IFM) contracts at high frequencies at a priming level of Ca2þ that stays constant during oscillations. The muscles are stretch-activated. Alternating contraction of opposing muscles produces resonant distortions of the thorax, which results in rapid movement of the wings. The TnC isoform, F1, which binds one Ca2þ in the C-lobe, is needed for stretch-activation. The N-lobe of F1 is inactive and does not bind TnH (the TnI of IFM). The C-lobe changes from a closed to open conformation on binding Ca2þ. However, the binding of TnH to this lobe is independent of Ca2þ, and the transition may be necessary for optimum orientation of TnH. The minor TnC isoform, F2, which is needed for the development of isometric force at relatively high [Ca2þ], binds one Ca2þ in each lobe; association with TnH involves both lobes and is Ca2þ-dependent. In Lethocerus IFM, the C-terminus of TnH is close to a crossbridge, and may form part of a ''troponin bridge'' between the thick and thin filament, transmitting strain to the thin filament on stretch. The inhibitory sequence of TnH would be pulled off actin by stretching, rather than by reversibly binding to the N-lobe of TnC in the presence of Ca2þ, as occurs in skeletal muscle. We will describe the effect of the C-terminal half of F1 alone on oscillatory contraction, and the effect of adding the C-terminal region of TnH to compete with endogenous TnH.

The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy

“…The resulting PL a of 107 nm for wild-type molecules agrees with previous determinations [5,6]. For the two mutants, we find PL a of ~80 nm, suggesting that the mutants are more curved and/or more flexible than the wild-type, in agreement with the trend observed in preliminary reports by others [15]. …”