Cardiomyopathy Mutation Alters End-to-End Junction of Tropomyosin and Reduces Calcium Sensitivity.

摘要: Abstract Muscle contraction is governed by tropomyosin (Tpm) shifting azimuthally between three states on F-actin (B-, C-, and M-states) in response to calcium binding troponin actomyosin cross-bridge formation. The Tpm coiled coil polymerizes head tail along the long-pitch helix of form continuous superhelical cables that wrap around actin filaments. end-to-end bonds formed N- C-terminus adjacent molecules define continuity play a critical role ability cooperatively bind actin, thus facilitating conformational switching propagate F-actin. We expect missense mutation this overlap region associated with dilated cardiomyopathy, A277V, will alter thin filament activation altering structure. Here, we used cosedimentation assays in vitro motility determine how alters its regulate interactions. Analytical viscometry coupled molecular dynamics simulations showed A277V results enhanced bond strength reduced curvature domain. mutant exhibited actin-Tpm affinity, consistent stabilization. observed A277V-induced decrease cooperative regulated indicates increased stabilization not correlated Tpm-Tpm or mechanical rigidity as often assumed. Instead, structural changes result local delocalized increases flexibility prominent coiled-coil twisting pseudorepeat 4. An Ca2+ sensitivity, mutation-induced bolstering B-state Tpm-actin electrostatic contacts an T1 was also observed.