Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin.
Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin.
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心肌病必需轻链突变揭示了调节肌凝蛋白超放松状态的机制。
DOI：
10.1085/jgp.202012801
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Szczesna-Cordary D
中科院分区：
文献类型：
--
作者：
Sitbon YH;Diaz F;Kazmierczak K;Liang J;Wangpaichitr M;Szczesna-Cordary D
Sitbon 等人利用与心肌病相关的突变。研究肌球蛋白超松弛状态和无序松弛状态之间的转变。他们的研究结果表明，肌球蛋白必需轻链的 N 末端控制着这两种状态之间的转变。在这项研究中，我们评估了两种心肌病病理模型和心脏肥大的近生理模型中肌球蛋白和肌节蛋白磷酸化的超松弛（SRX）状态。心肌病模型的疾病进展和严重程度有所不同，并表达由 MYL3 基因编码的人心室肌球蛋白必需轻链 (ELC) 的肥厚性 (HCM-A57G) 或限制性 (RCM-E143K) 突变。将它们的效果与以 N 末端截短的 ELC（Δ43 ELC 小鼠）为代表的近生理性心脏重塑以及未突变的人心室 WT-ELC 小鼠进行比较。 HCM-A57G 和 RCM-E143K 突变对 ATP 依赖性肌球蛋白能量状态具有拮抗作用，HCM-A57G 跨桥促进无序松弛 (DRX) 状态，而 RCM-E143K 模型有利于能量守恒的 SRX 状态。 HCM-A57G 模型促进了从 SRX 到 DRX 状态的转换，并且与正常 WT-ELC 心肌的 RLC 相比，肌球蛋白调节轻链 (RLC) 磷酸化增加了约 40%。相反，与 WT-ELC 的 RLC 相比，RCM-E143K 相关的 SRX 状态稳定伴随着肌球蛋白 RLC 磷酸化水平大约低两倍。与 WT-ELC 心脏相比，在 Δ43 心脏中也观察到 RLC 磷酸化的上调，并且 Δ43 肌球蛋白有利于节能的 SRX 构象。这两种疾病变异对力瞬变的持续时间也有不同的影响，在这些病理模型的电刺激乳头肌中测量到较短的（HCM-A57G）或较长的（RCM-E143K）瞬变，而Δ43纤维没有显示任何变化。我们提出，Δ43 小鼠心脏中缺失的 ELC (N-ELC) N 末端作为能量开关，促进 SRX 到 DRX 的转变，并通过分别促进或立体阻断 HCM-A57G 和 RCM-E143K 心脏中的 RLC 磷酸化，从而有助于调节全长 ELC 小鼠中的肌球蛋白 RLC 磷酸化。
Using mutations associated with cardiomyopathy, Sitbon et al. study the transition between the super relaxed state of myosin and the disordered-relaxed state. Their findings suggest that the N terminus of myosin essential light chain controls the transition between these two states. In this study, we assessed the super relaxed (SRX) state of myosin and sarcomeric protein phosphorylation in two pathological models of cardiomyopathy and in a near-physiological model of cardiac hypertrophy. The cardiomyopathy models differ in disease progression and severity and express the hypertrophic (HCM-A57G) or restrictive (RCM-E143K) mutations in the human ventricular myosin essential light chain (ELC), which is encoded by the MYL3 gene. Their effects were compared with near-physiological heart remodeling, represented by the N-terminally truncated ELC (Δ43 ELC mice), and with nonmutated human ventricular WT-ELC mice. The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state. The HCM-A57G model promoted the switch from the SRX to DRX state and showed an ∼40% increase in myosin regulatory light chain (RLC) phosphorylation compared with the RLC of normal WT-ELC myocardium. On the contrary, the RCM-E143K–associated stabilization of the SRX state was accompanied by an approximately twofold lower level of myosin RLC phosphorylation compared with the RLC of WT-ELC. Upregulation of RLC phosphorylation was also observed in Δ43 versus WT-ELC hearts, and the Δ43 myosin favored the energy-saving SRX conformation. The two disease variants also differently affected the duration of force transients, with shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles from these pathological models, while no changes were displayed by Δ43 fibers. We propose that the N terminus of ELC (N-ELC), which is missing in the hearts of Δ43 mice, works as an energetic switch promoting the SRX-to-DRX transition and contributing to the regulation of myosin RLC phosphorylation in full-length ELC mice by facilitating or sterically blocking RLC phosphorylation in HCM-A57G and RCM-E143K hearts, respectively.
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影响因子：
10.8
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
通讯作者：
Rabinovitch, Peter S.
影响因子：
4.8
作者：
Bourens, Myriam;Barrientos, Antoni
通讯作者：
Barrientos, Antoni
DOI：
10.1073/pnas.1602776113
发表时间：
2016-05-24
影响因子：
11.1
作者：
Kampourakis, Thomas;Sun, Yin-Biao;Irving, Malcolm
通讯作者：
Irving, Malcolm
影响因子：
3.4
作者：
Guhathakurta, Piyali;Prochniewicz, Ewa;Thomas, David D.
通讯作者：
Thomas, David D.
DOI：
10.1152/ajpheart.00107.2013
发表时间：
2013-08-01
影响因子：
4.8
作者：
Kazmierczak, Katarzyna;Paulino, Ellena C.;Szczesna-Cordary, Danuta
通讯作者：
Szczesna-Cordary, Danuta