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人类NALCN通道的结构获解析
2021-12-24 23:32
来源：小柯机器人

美国基因泰克公司Jian Payandeh等研究人员合作揭示人类NALCN通道的结构。这一研究成果于2021年12月20日在线发表在国际学术期刊《自然》上。

据介绍，由NALCN通道携带的去极化钠（Na+）泄漏电流调节许多神经元的静止膜电位，进而调节呼吸、昼夜节律、运动和疼痛敏感性。NALCN需要FAM155A、UNC79和UNC80来发挥作用，但这些辅助亚基的作用还不清楚。NALCN、UNC79和UNC80在啮齿动物中是必不可少的，而人类NALCN和UNC80的突变会导致严重的发育和神经系统疾病。
 
关于NALCN通道的组成、组装和门控的基本方面仍不清楚，研究人员确定了这个约1兆道尔顿的复合物结构。UNC79和UNC80是巨大的HEAT重复蛋白，形成一个交织的反平行超螺旋组件，在细胞内对接NALCN-FAM155A孔形成的亚复合体。钙调蛋白与NALCN的羧基末端结构域共存，从而确定该区域为一个潜在的调节中心。单通道分析发现野生型复合物的开放概率很低，这突出了结构中紧闭的S6门，并为解释致病变体的门控特性改变提供了基础。UNC79-UNC80亚复合物与NALCN DI-DII和DII-DIII连接体之间的关键制约因素被确定，从而形成了一个通道体门控模型。这些研究结果为了解NALCN通道的生理结构提供了一个结构蓝图，并为调节静止膜电位的药物发现提供了模板。
 
附：英文原文
 
Title: Structural architecture of the human NALCN channelosome

Author: Kschonsak, Marc, Chua, Han Chow, Weidling, Claudia, Chakouri, Nourdine, Noland, Cameron L., Schott, Katharina, Chang, Timothy, Tam, Christine, Patel, Nidhi, Arthur, Christopher P., Leitner, Alexander, Ben-Johny, Manu, Ciferri, Claudio, Pless, Stephan Alexander, Payandeh, Jian

Issue&Volume: 2021-12-20

Abstract: Depolarizing sodium (Na+) leak currents carried by the NALCN channel regulate the resting membrane potential of many neurons to modulate respiration, circadian rhythm, locomotion and pain sensitivity1–8. NALCN requires FAM155A, UNC79 and UNC80 to function, but the role of these auxiliary subunits is not understood3,7,9–12. NALCN, UNC79 and UNC80 are essential in rodents2,9,13, and mutations in human NALCN and UNC80 cause severe developmental and neurological disease14,15. Since fundamental aspects about the composition, assembly, and gating of the NALCN channelosome remain obscure, we determined the structure of this ~1 megadalton complex. UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly which docks intracellularly onto the NALCN-FAM155A pore-forming subcomplex. Calmodulin copurifies bound to the carboxy-terminal domain of NALCN, identifying this region as a putative modulatory hub. Single channel analyses uncovered a low open probability for the wild-type complex, highlighting the tightly closed S6-gate in the structure, and providing a basis to interpret the altered gating properties of disease-causing variants. Key constraints between the UNC79-UNC80 subcomplex and the NALCN DI-DII and DII-DIII linkers are identified that lead to a model of channelosome gating. Our results provide a structural blueprint to understand NALCN channelosome physiology and a template for drug discovery to modulate the resting membrane potential.

DOI: 10.1038/s41586-021-04313-5

Source: https://www.nature.com/articles/s41586-021-04313-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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