Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.
Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.
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DOI：
10.1016/j.abb.2016.02.004
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发表时间：
2016-07-01
影响因子：
3.9
通讯作者：
Regnier M
中科院分区：
文献类型：
--
作者：
Cheng Y;Regnier M
心肌肌钙蛋白（cTn）作为肌肉收缩和松弛的关键调节因子，由三个不同的亚基组成（cTnC：高度保守的Ca2+结合亚基，cTnI：肌动球蛋白atp酶抑制亚基，cTnT：原肌球蛋白结合亚基）。在这篇综述中，我们简要总结了cTn及其亚基的结构-功能关系，pka介导的cTnI磷酸化对其的调节，以及肥厚性心肌病（HCM）相关cTnI突变如何改变这些特性的已知情况。这包括最近使用计算建模方法来理解疾病相关突变的原子结构水平基础的工作。我们提出了一种观点，即cTnC-cTnI相互作用的改变（而不是cTn的Ca2+结合特性）本身破坏了pka介导的cTnI Ser-23/24磷酸化的能力，从而改变了至少一些hcm相关突变的收缩和松弛。最先进的生物物理方法的结合可以为导致cTnI突变的收缩功能障碍的结构-功能机制提供新的见解，并为心脏病的诊断、预防甚至治疗提供令人兴奋的新途径。
Cardiac troponin (cTn) acts as a pivotal regulator of muscle contraction and relaxation and is composed of three distinct subunits (cTnC: a highly conserved Ca2+ binding subunit, cTnI: an actomyosin ATPase inhibitory subunit, and cTnT: a tropomyosin binding subunit). In this mini-review, we briefly summarize the structure-function relationship of cTn and its subunits, its modulation by PKA-mediated phosphorylation of cTnI, and what is known about how these properties are altered by hypertrophic cardiomyopathy (HCM) associated mutations of cTnI. This includes recent work using computational modeling approaches to understand the atomic-based structural level basis of disease-associated mutations. We propose a viewpoint that it is alteration of cTnC-cTnI interaction (rather than the Ca2+ binding properties of cTn) per se that disrupt the ability of PKA-mediated phosphorylation at cTnI Ser-23/24 to alter contraction and relaxation in at least some HCM-associated mutations. The combination of state of the art biophysical approaches can provide new insight on the structure-function mechanisms of contractile dysfunction resulting cTnI mutations and exciting new avenues for the diagnosis, prevention, and even treatment of heart diseases.