Assembly of synaptic active zones requires phase separation of scaffold molecules.

Nature
Nathan A McDonaldKang Shen

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 c...Continue Reading

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Citations

Jan 19, 2021·Current Opinion in Cell Biology·Khuloud Jaqaman, Jonathon A Ditlev
Mar 4, 2021·ELife·Javier Emperador-MeleroPascal S Kaeser
Mar 22, 2021·Journal of Molecular Biology·G Campbell CarterXin Zhang
Apr 4, 2021·Cells·Minchuan Zhang, George J Augustine
Apr 20, 2021·Frontiers in Cell and Developmental Biology·Xingqiao XieZhiyi Wei
May 13, 2021·Current Opinion in Neurobiology·Nathan A McDonald, Kang Shen
May 26, 2021·Nature Communications·Javier Emperador-MeleroPascal S Kaeser
Jun 6, 2021·Neuropharmacology·Yuko FukataMasaki Fukata
Oct 17, 2021·Oncogene·Henna PehkonenOuti Monni

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Methods Mentioned

BETA
fluorescence recovery after photobleaching
two-hybrid
electron microscopy
PCR

Software Mentioned

Prism
Fiji
GraphPad
ImageJ

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