Products Cited in Publications Worldwide Intracellular protein-lipid interactions drive presynaptic assembly prior to neurexin recruitment

Intracellular protein-lipid interactions drive presynaptic assembly prior to neurexin recruitment

Frankel, Elisa B; Tiroumalechetty, Araven; Su, Zhaoqian; Henry, Parise S; Mueller, Brian D; Jorgensen, Erik M; Wu, Yinghao; Kurshan, Peri T

DOI: PMID:

Abstract

Neurexin cell-adhesion molecules regulate synapse development and function by recruiting synaptic components. Here, we uncover a mechanism for presynaptic assembly that precedes neurexin recruitment, mediated by interactions between cytosolic proteins and membrane phospholipids. Developmental imaging in C. elegans reveals that the intracellular active zone protein SYD-1 accumulates at nascent presynapses prior to its binding partner neurexin. Combining molecular dynamics simulations to model intrinsic interactions between SYD-1 and lipid bilayers with biochemical and in vivo validation of these predictions, we find that PIP2-interacting residues in the SYD-1 C2 domain are required for active zone assembly. Genetic perturbation of a PIP2-generating enzyme disrupts synaptic SYD-1 accumulation, while the PIP2-interacting domain of mammalian RIM1 can compensate for the SYD-1 C2 domain, suggesting functional homology between these proteins. Finally, we propose that the evolutionarily conserved g-neurexin isoform represents a minimal neurexin sequence that stabilizes nascent presynaptic assemblies, potentially a core function of this isoform.

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