Cardiac myosin filaments are directly regulated by calcium.
Cardiac myosin filaments are directly regulated by calcium.
复制标题
DOI：
10.1085/jgp.202213213
复制
发表时间：
2022-12-05
影响因子：
3.8
通讯作者：
Irving, Thomas C.
中科院分区：
文献类型：
--
作者：
Ma, Weikang;Nag, Suman;Gong, Henry;Qi, Lin;Irving, Thomas C.
钙诱导肌球蛋白头部的结构转变，从靠近粗丝的有序关闭状态到靠近细丝的无序打开状态，这与肌球蛋白从超松弛状态到无序松弛状态的生化转变有关。经典地，横纹肌收缩是由含肌动蛋白的细丝上的调节蛋白的钙（Ca 2+）依赖性结构变化启动的，其允许肌球蛋白马达的结合以产生力。此外，肌球蛋白静止状态和肌球蛋白活性状态之间的动态转换已被证明可调节肌肉收缩性，这是一种最近通过新型肌球蛋白靶向治疗剂验证的机制。然而，这种转换的分子本质尚不清楚。在这里，使用组合的小角度X-射线纤维衍射和生化分析与重建系统，我们表明，心脏粗丝直接Ca 2+调节。我们发现，Ca 2+诱导肌球蛋白头的结构转变从有序关闭状态接近粗丝到无序状态接近细丝。生物化学分析显示，在合成粗丝中，Ca 2+诱导的从非活性超松弛（SRX）状态到活性无序松弛（DRX）状态的转变。我们表明，这些转换是一个内在的特性，只有当组装成厚丝，并提供了一个新的视角自然界的两个正交的机制来调节肌肉收缩，通过薄和厚丝的心脏肌球蛋白。
Calcium induces a structural transition of myosin heads from ordered off states close to the thick filament to disordered on states near the thin filaments associated with a biochemical shift from the super-relaxed state(s) to the disordered-relaxed state(s) of myosin. Classically, striated muscle contraction is initiated by calcium (Ca2+)-dependent structural changes in regulatory proteins on actin-containing thin filaments, which allow the binding of myosin motors to generate force. Additionally, dynamic switching between resting off and active on myosin states has been shown to regulate muscle contractility, a recently validated mechanism by novel myosin-targeted therapeutics. The molecular nature of this switching, however, is not understood. Here, using a combination of small-angle x-ray fiber diffraction and biochemical assays with reconstituted systems, we show that cardiac thick filaments are directly Ca2+-regulated. We find that Ca2+ induces a structural transition of myosin heads from ordered off states close to the thick filament to disordered on states closer to the thin filaments. Biochemical assays show a Ca2+-induced transition from an inactive super-relaxed (SRX) state(s) to an active disordered-relaxed (DRX) state(s) in synthetic thick filaments. We show that these transitions are an intrinsic property of cardiac myosin only when assembled into thick filaments and provide a fresh perspective on nature’s two orthogonal mechanisms to regulate muscle contraction through the thin and the thick filaments.
登录
查看更多内容
影响因子：
3.4
作者：
Ma W;Gong H;Jani V;Lee KH;Landim-Vieira M;Papadaki M;Pinto JR;Aslam MI;Cammarato A;Irving T
通讯作者：
Irving T
影响因子：
5.6
作者：
HUXLEY, HE;BROWN, W
通讯作者：
BROWN, W
DOI：
10.1073/pnas.1809540115
发表时间：
2018-08-28
影响因子：
11.1
作者：
Anderson, Robert L.;Trivedi, Darshan V.;Spudich, James A.
通讯作者：
Spudich, James A.
影响因子：
5.6
作者：
Markandran K;Poh JW;Ferenczi MA;Cheung C
通讯作者：
Cheung C
DOI：
10.1073/pnas.1804726115
发表时间：
2018-10-09
影响因子：
11.1
作者：
Kiss B;Lee EJ;Ma W;Li FW;Tonino P;Mijailovich SM;Irving TC;Granzier HL
通讯作者：
Granzier HL