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Abstract
Striated muscle tropomyosin spans seven actin monomers and contains seven quasi-repeating regions with loose sequence similarity. Each region contains a hypothesized actin binding motif. To examine the functions of these regions, full-length tropomyosin was compared with tropomyosin internal deletion mutants spanning either five or four actins. Actin-troponin-tropomyosin filaments lacking tropomyosin regions 2-3 exhibited calcium-sensitive regulation in in vitro motility and myosin S1 ATP hydrolysis experiments, similar to filaments with full-length tropomyosin. In contrast, filaments lacking tropomyosin regions 3-4 were inhibitory to these myosin functions. Deletion of regions 2-4, 3-5, or 4-6 had little effect on tropomyosin binding to actin in the presence of troponin or troponin-Ca(2+), or in the absence of troponin. However, all of these mutants inhibited myosin cycling. Deletion of the quasi-repeating regions diminished the prominent effect of myosin S1 on tropomyosin-actin binding. Interruption of this cooperative, myosin-tropomyosin interaction was least severe for the mutant lacking regions 2-3 and therefore correlated with inhibition of myosin cycling. Regions 3, 4, and 5 each contributed about 1.5 kcal/mol to this process, whereas regions 2 and 6 contributed much less. We suggest that a myosin-induced conformational change in actin facilitates the azimuthal repositioning of tropomyosin which is an essential part of regulation.
Highlights
Cardiac and skeletal muscle contractions are regulated by calcium- and myosin-induced alterations in the conformation of the thin filament [1,2,3]
An important component of these conformational changes is believed to be azimuthal repositioning of tropomyosin, which unblocks sites on actin which bind to myosin. (A dissenting viewpoint is presented in Ref. 4.) Recent structural studies indicate that most of this unblocking occurs when calcium binds to troponin-tropomyosin but that the myosin binding site is not fully exposed in the calcium conformation of the thin filament [5,6,7]
It was suggested that its inhibitory properties were caused by destabilization of the myosin-induced conformation of the thin filament, the conformation corresponding to full azimuthal movement of tropomyosin
Summary
Cardiac and skeletal muscle contractions are regulated by calcium- and myosin-induced alterations in the conformation of the thin filament [1,2,3]. Several functional changes in the thin filament occur when myosin is bound (8 – 17), and recent structural data show that in this circumstance tropomyosin undergoes a smaller, additional azimuthal movement [5]. This results in full exposure of the myosin binding site on actin. These previous data suggest that the deleted portion of tropomyosin is somehow important for thin filament activation, but they do not identify the specific structural changes in ⌬234Tm which are responsible for its altered function. A broad internal region of tropomyosin is important for tropomyosin binding to myosin S1-decorated actin, and the strength of this binding process correlates with retention of physiological troponin-tropomyosin-mediated regulation
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