KBTBD13 is an actin-binding protein that modulates muscle kinetics
KBTBD13 is an actin-binding protein that modulates muscle kinetics
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DOI：
10.1172/jci124000
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发表时间：
2020-02-03
影响因子：
15.9
通讯作者：
Ottenheijm，Coen A. C.
中科院分区：
文献类型：
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作者：
de Winter，Josine M.;Molenaar，Joery P.;Ottenheijm，Coen A. C.
调节肌肉松弛动力学的机制对肌肉功能至关重要。松弛动力学受损影响的一个主要例子是inKBTBD13（NEM6）突变引起的线状肌病。除了虚弱外，NEM6患者肌肉松弛缓慢，影响收缩力和日常生活活动。KBTBD13在肌肉中的作用尚不清楚，NEM6的病理机制也不确定。经颅磁刺激诱导的肌肉松弛、肌纤维和肌节收缩性分析、低角度x射线衍射和超分辨率显微镜的结合显示，NEM6患者的肌肉松弛动力学受损是由细丝（一种肌肉微观结构）的结构变化引起的。通过对重组KBTBD13、敲除KBTBD13和敲除kbtbd13r408c小鼠模型以及gfp标记的转基因KBTBD13斑马鱼模型的同源性建模、结合和收缩性分析，我们发现KBTBD13与肌动蛋白（细丝的主要成分）结合，inkbtbd13突变导致结构改变，损害肌肉松弛动力学。我们认为这种基于肌动蛋白的松弛受损是NEM6病理的核心。
The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations inKBTBD13(NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation–induced muscle relaxation, muscle fiber– and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13,Kbtbd13-knockout andKbtbd13R408C-knockin mouse models, and a GFP-labeledKbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin — a major constituent of the thin filament — and that mutations inKBTBD13cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.