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支架分子相分离有助于突触活性区的组装
2020-11-20 13:59

美国斯坦福大学Kang Shen课题组的最新研究发现突触活性区的组装需要支架分子蛋白发生相分离。2020年11月18日出版的《自然》在线发表了这项成果。

研究人员发现核心活性区支架蛋白SYD-2(也称为脂蛋白-α)和ELKS-1在突触发育的早期阶段会发生相分离,并随后成熟为固体结构。研究人员通过使用突变的SYD-2和ELKS-1蛋白(具体缺乏这种活性)直接测试了体内相分离的功能。这些突变蛋白在秀丽隐杆线虫的突触中仍可富集,但缺乏活性区组装和突触功能缺陷。通过从无关蛋白中引入相分离基序可以弥补这些缺陷。

在体外,研究人员重构了SYD-2和ELKS-1液相支架,并发现它能够结合下游活性区的成分。研究人员发现SYD-2和ELKS-1液滴的流动性对于活性区组分的有效混合和结合至关重要。这些数据表明,在成熟为稳定的最终结构之前,支架分子形成的液滴对于突触活性区的组装至关重要。

据了解,神经元发育过程中突触的形成对于神经回路和神经系统的形成至关重要。每个神经前突触都会形成一个核心的“活性区”结构,在该结构中离子通道聚集,突触小泡释放其神经递质。尽管已有研究表明活性区的组成,但尚不清楚活性区蛋白如何组装在一起并招募发育过程中囊泡释放所需的分子。

附:英文原文

Title: Assembly of synaptic active zones requires phase separation of scaffold molecules

Author: Nathan A. McDonald, Richard D. Fetter, Kang Shen

Issue&Volume: 2020-11-18

Abstract: The formation of synapses during neuronal development is essential for establishing neural circuits and a nervous system1. Every presynapse builds a core ‘active zone’ structure, where ion channels cluster and synaptic vesicles release their neurotransmitters2. Although the composition of active zones is well characterized2,3, it is unclear how active-zone proteins assemble together and recruit the machinery required for vesicle release during development. Here we find that the core active-zone scaffold proteins SYD-2 (also known as liprin-α) and ELKS-1 undergo phase separation during an early stage of synapse development, and later mature into a solid structure. We directly test the in vivo function of phase separation by using mutant SYD-2 and ELKS-1 proteins that specifically lack this activity. These mutant proteins remain enriched at synapses in Caenorhabditis elegans, but show defects in active-zone assembly and synapse function. The defects are rescued by introducing a phase-separation motif from an unrelated protein. In vitro, we reconstitute the SYD-2 and ELKS-1 liquid-phase scaffold, and find that it is competent to bind and incorporate downstream active-zone components. We find that the fluidity of SYD-2 and ELKS-1 condensates is essential for efficient mixing and incorporation of active-zone components. These data reveal that a developmental liquid phase of scaffold molecules is essential for the assembly of the synaptic active zone, before maturation into a stable final structure.

DOI: 10.1038/s41586-020-2942-0

Source: https://www.nature.com/articles/s41586-020-2942-0

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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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