| RRC ID |
84167
|
| Author |
Frankel EB, Tiroumalechetty A, Su Z, Henry PS, Mueller BD, Jorgensen EM, Wu Y, Kurshan PT.
|
| Title |
Intracellular protein-lipid interactions drive presynaptic assembly prior to neurexin recruitment.
|
| Journal |
Neuron
|
| 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 γ-neurexin isoform represents a minimal neurexin sequence that stabilizes nascent presynaptic assemblies, potentially a core function of this isoform.
|
| Volume |
113(5)
|
| Pages |
737-753.e6
|
| Published |
2025-3-5
|
| DOI |
10.1016/j.neuron.2024.12.017
|
| PII |
S0896-6273(24)00916-4
|
| PMID |
39814011
|
| PMC |
PMC11886894
|
| MeSH |
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins* / genetics
Caenorhabditis elegans Proteins* / metabolism
Molecular Dynamics Simulation
Presynaptic Terminals* / metabolism
Synapses* / metabolism
|
| Resource |
| C.elegans |
tm1233 |
