小柯机器人

美国麻省大学陈医学院Roger Craig、Raúl Padrón和Debabrata Dutta课题组合作取得一项新突破。他们的研究揭示了人心脏肌球蛋白丝的冷冻电镜结构。这一研究成果于2023年11月1日发表在国际学术期刊《自然》上。

研究人员利用冷冻电镜解析了人类心肌肌球蛋白丝主要（含心肌肌球蛋白结合蛋白C（cMyBP-C））区域的结构。重建的结构揭示了肌联蛋白（titin）和cMyBP-C的结构，并揭示了肌球蛋白的马达结构域（头部）如何形成三种不同类型的结构域（提供功能灵活性），它们相互之间以及与titin和cMyBP-C相互作用，从而决定了心肌丝的结构和功能。研究人员还解析了肌球蛋白尾部在丝状骨架中的排列。

该结构揭示了cMyBP-C如何参与心脏超放松状态的产生；titin和cMyBP-C如何促进长度依赖性激活；以及肌球蛋白和cMyBP-C的突变如何干扰相互作用，从而导致疾病产生。该结构重建解决了过去未知的心肌功能，并整合了以往与心肌结构和功能有关的数据。它为解释心肌的结构、生理和功能提供了参考。

据了解，心脏泵血的动力来源于运动蛋白肌球蛋白丝，肌球蛋白拉动肌动蛋白丝产生心脏收缩。除肌球蛋白外，心肌肌丝还含有cMyBP-C和titin，前者可在生理刺激下调节收缩力，后者则是心肌肌丝组装的支架。肌球蛋白、cMyBP-C和titin都可能发生突变，从而导致心力衰竭。尽管心肌肌球蛋白丝对生命至关重要，但其分子结构一直是个谜。

附：英文原文

Title: Cryo-EM structure of the human cardiac myosin filament

Author: Dutta, Debabrata, Nguyen, Vu, Campbell, Kenneth S., Padrn, Ral, Craig, Roger

Issue&Volume: 2023-11-01

Abstract: Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly1. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60years2. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin’s motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state3; how titin and cMyBP-C may contribute to length-dependent activation4; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease5,6. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.

DOI: 10.1038/s41586-023-06691-4

Source: https://www.nature.com/articles/s41586-023-06691-4

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