Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Biophys J. 2011 Jun 22;100(12):2964-73. doi: 10.1016/j.bpj.2011.05.010.
The molecular motor protein myosin VI moves toward the minus-end of actin filaments with a step size of 30-36 nm. Such large step size either drastically limits the degree of complex formation between dimer subunits to leave enough length for the lever arms, or requires an extension of the lever arms' crystallographically observed structure. Recent experimental work proposed that myosin VI dimerization triggers the unfolding of the protein's proximal tail domain which could drive the needed lever-arm extension. Here, we demonstrate through steered molecular dynamics simulation the feasibility of sufficient extension arising from turning a three-helix bundle into a long α-helix. A key role is played by the known calmodulin binding that facilitates the extension by altering the strain path in myosin VI. Sequence analysis of the proximal tail domain suggests that further calmodulin binding sites open up when the domain's three-helix bundle is unfolded and that subsequent calmodulin binding stabilizes the extended lever arms.
分子马达肌球蛋白 VI 以 30-36nm 的步长向肌动蛋白纤维的负端移动。如此大的步长要么极大地限制了二聚体亚基之间的复杂形成程度，从而为臂留出足够的长度，要么需要延伸臂的晶体观察结构。最近的实验工作提出，肌球蛋白 VI 二聚化触发了蛋白质近端尾部结构域的展开，这可能驱动所需的臂延伸。在这里，我们通过导向分子动力学模拟证明了从三螺旋束转变成长α-螺旋足以实现足够的延伸。一个关键作用是已知的钙调蛋白结合，通过改变肌球蛋白 VI 中的应变路径来促进延伸。对近端尾部结构域的序列分析表明，当该结构域的三螺旋束展开时，进一步的钙调蛋白结合位点被打开，随后钙调蛋白结合稳定了延伸的臂。
