Human skeletal myopathy myosin mutations disrupt myosin head sequestration.
Human skeletal myopathy myosin mutations disrupt myosin head sequestration.
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DOI：
10.1172/jci.insight.172322
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发表时间：
2023-11-08
期刊：
影响因子：
8
通讯作者：
Ochala, Julien
中科院分区：
文献类型：
--
作者：
Carrington, Glenn;Hau, Abbi;Kosta, Sarah;Dugdale, Hannah F.;Muntoni, Francesco;D'Amico, Adele;Van den Bergh, Peter;Romero, Norma B.;Malfatti, Edoardo;Vilchez, Juan Jesus;Oldfors, Anders;Pajusalu, Sander;Ounap, Katrin;Giralt-Pujol, Marta;Zanoteli, Edmar;Campbell, Kenneth S.;Iwamoto, Hiroyuki;Peckham, Michelle;Ochala, Julien
由MYH7和MYH2编码的肌球蛋白重链在人体骨骼肌中含量丰富，对肌肉收缩很重要。然而，目前尚不清楚这些基因的突变是如何扰乱肌球蛋白的结构和功能，从而导致称为肌球蛋白病的骨骼肌肌病。在这里，我们使用多种方法来分析肌球蛋白轻质肌球蛋白(LMM)区域常见的MYH7和MYH2突变的影响。表达和纯化的MYH7和MYH2 LMM突变蛋白结合计算机模拟的分析表明，肌球蛋白卷曲的卷曲结构和体外微丝的堆积通常被破坏。使用患者的肌肉活检和荧光ATP类似物追踪方案估计肌球蛋白超松弛的比例，结合X射线衍射测量估计肌球蛋白头部的顺序，我们发现在体内基础肌球蛋白ATP消耗增加，肌球蛋白超松弛状态减少。此外，研究肌纤维收缩功能的肌纤维力学实验表明，肌纤维的收缩性能没有受到影响。这些发现表明，与LMM突变相关的结构重塑导致关闭头的形成受到损害，从而增加了细丝对肌球蛋白头ATP的需求，而不是影响收缩能力。这些关键发现将有助于设计未来肌球蛋白病的治疗方法。
Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.
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影响因子：
6
作者：
Ochala J;Finno CJ;Valberg SJ
通讯作者：
Valberg SJ
影响因子：
2.9
作者：
Krivov, Georgii G.;Shapovalov, Maxim V.;Dunbrack, Roland L., Jr.
通讯作者：
Dunbrack, Roland L., Jr.
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：
3.7
作者：
McNamara, James W.;Li, Amy;dos Remedios, Cristobal G.
通讯作者：
dos Remedios, Cristobal G.
影响因子：
3
作者：
Offer, G;Hicks, MR;Woolfson, DN
通讯作者：
Woolfson, DN