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Structural switch in acetylcholine receptors in developing muscle
Nature ( IF 50.5 ) Pub Date : 2024-07-31 , DOI: 10.1038/s41586-024-07774-6
Huanhuan Li 1 , Jinfeng Teng 1 , Ryan E Hibbs 1, 2
Affiliation  

During development, motor neurons originating in the brainstem and spinal cord form elaborate synapses with skeletal muscle fibres1. These neurons release acetylcholine (ACh), which binds to nicotinic ACh receptors (AChRs) on the muscle, initiating contraction. Two types of AChR are present in developing muscle cells, and their differential expression serves as a hallmark of neuromuscular synapse maturation2,3,4. The structural principles underlying the switch from fetal to adult muscle receptors are unknown. Here, we present high-resolution structures of both fetal and adult muscle nicotinic AChRs, isolated from bovine skeletal muscle in developmental transition. These structures, obtained in the absence and presence of ACh, provide a structural context for understanding how fetal versus adult receptor isoforms are tuned for synapse development versus the all-or-none signalling required for high-fidelity skeletal muscle contraction. We find that ACh affinity differences are driven by binding site access, channel conductance is tuned by widespread surface electrostatics and open duration changes result from intrasubunit interactions and structural flexibility. The structures further reveal pathogenic mechanisms underlying congenital myasthenic syndromes.



中文翻译:


肌肉发育过程中乙酰胆碱受体的结构转换



在发育过程中,起源于脑干和脊髓的运动神经元与骨骼肌纤维形成复杂的突触1 。这些神经元释放乙酰胆碱 (ACh),乙酰胆碱与肌肉上的烟碱性 ACh 受体 (AChR) 结合,启动收缩。发育中的肌肉细胞中存在两种类型的 AChR,它们的差异表达是神经肌肉突触成熟的标志2,3,4 。从胎儿肌肉受体转变为成人肌肉受体的结构原理尚不清楚。在这里,我们展示了从发育过渡阶段的牛骨骼肌中分离出来的胎儿和成人肌肉烟碱 AChR 的高分辨率结构。这些结构是在乙酰胆碱不存在和存在的情况下获得的,为理解胎儿与成人受体亚型如何调整突触发育与高保真骨骼肌收缩所需的全或无信号传导提供了结构背景。我们发现ACh亲和力差异是由结合位点访问驱动的,通道电导是由广泛的表面静电调节的,开放持续时间的变化是由亚基内相互作用和结构灵活性引起的。这些结构进一步揭示了先天性肌无力综合征的致病机制。

更新日期:2024-08-02
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