Two common types of cardiovascular disease are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) which occur from changes to sarcomere contractile mechanisms and activity. Actin amino acid substitutions R312C and R312H have been found in HCM and DCM patients, respectively. Previously, we observed that R312C/H variants display both hyperactivity and hypoactivity in vitro, contradicting traditional characterizations of HCM and DCM-causing variants. Here, we further characterized R312C/H actin variants in vitro and conducted in silico modelling to better understand the mechanisms differentiating HCM and DCM. Our results suggest that R312C/H substitutions cause structural changes that differentially impact actomyosin activity. A gradient of altered interactions with regulatory proteins troponin, tropomyosin, and the C0C2 domains of myosin binding protein C was also observed, influencing the accessibility of active and inhibitory conformations of these proteins. The results presented here support our previous suggestion of a gradient of factors that differentiate between HCM and DCM. Further characterization of HCM and DCM-causing actin variants using in vitro and in silico methods is required for better understanding cardiomyopathy and improving clinical outcomes.

中文翻译：

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疾病中的二元性：肌动蛋白残基 312 的两个氨基酸取代如何导致相反形式的心肌病。


两种常见的心血管疾病类型是肥厚型心肌病 （HCM） 和扩张型心肌病 （DCM），它们是由肌节收缩机制和活动的变化引起的。肌动蛋白氨基酸取代 R312C 和 R312H 分别在 HCM 和 DCM 患者中被发现。以前，我们观察到 R312C/H 变体在体外表现出多动和低活性，这与 HCM 和导致 DCM 的变体的传统特征相矛盾。在这里，我们进一步表征了体外 R312C/H 肌动蛋白变体，并在计算机建模中进行了表征，以更好地了解区分 HCM 和 DCM 的机制。我们的结果表明，R312C/H 取代引起结构变化，从而对肌动球蛋白活性产生差异性影响。还观察到与调节蛋白肌钙蛋白、原肌球蛋白和肌球蛋白结合蛋白 C 的 C0C2 结构域相互作用的改变梯度，影响这些蛋白质的活性和抑制构象的可及性。这里提供的结果支持我们之前提出的区分 HCM 和 DCM 的因素梯度的建议。为了更好地了解心肌病和改善临床结局，需要使用体外和计算机方法进一步表征 HCM 和导致 DCM 的肌动蛋白变异。