Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation
- 1Georgia Institute of Technology
Abstract
The precise formation of synapses ensures the proper wiring and function of nervous systems. Specific synapse formation is controlled by synaptic adhesion molecules, which link pre- and post-synaptic cells. Despite this central role, details of how adhesion molecules organize and signal intracellularly to build core synaptic structures are limited. Here, we identify multiple tyrosine phosphorylation sites on the cytoplasmic tail of the C. elegans SYG-1 synaptic adhesion molecule that are critical to initiate presynapse formation. We determine that SRC-1 and SRC-2 tyrosine kinases are redundantly responsible for SYG-1 phosphorylation and are consequently critical for presynapse assembly. The phosphorylated population of SYG-1 localizes in clusters within a larger SYG-1 pool and these clusters mark sites of presynaptic active zone assembly. Reconstitution of SYG-1 clusters in vitro with SH2-domain adapters and WSP-1 reveals a dynamic biomolecular condensate-forming system. Blocking phosphotyrosine adapters and condensate formation in vivo results in the loss of SYG-1 clusters, defective presynapse formation, and compromised neurotransmission. We conclude that phosphorylation of a subpopulation of synaptic adhesion molecules activates and organizes them into condensate-based clusters to initiate presynapse formation.
Related
- Grb2 phosphorylation antagonizes EGFR-driven ras activation by interfering with condensate assembly
- LIF-LIFR/gp130 Survival Signaling and Connexin 47 Dysregulation upon Murine-β-Coronavirus Infection: Discovery of a Novel ERK2 Phosphorylation Site at Cx47 C-Terminal Domain
- CD28 costimulation is organized by signaling condensates and counteracted by PD-1
- VASH1 phosphorylation regulates tubulin detyrosination via CNP/PRKG1α signaling in DRG neurons.
- SVEP1 enables efficient binding of angiopoietin-2 to the TIE1 receptor, allowing receptor phosphorylation and downstream signaling
BibTeX
@misc{wu2026synaptic,
title = {{Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation}},
author = {S. Wu and N. A. Morales and D. R. Li and N. A. McDonald},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.747070},
url = {https://www.biorxiv.org/content/10.64898/2026.08.25.747070v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation
AU - S. Wu
AU - N. A. Morales
AU - D. R. Li
AU - N. A. McDonald
PY - 2026
DA - 2026/08/25
PB - bioRxiv
DO - 10.64898/2026.08.25.747070
UR - https://www.biorxiv.org/content/10.64898/2026.08.25.747070v1
AB - The precise formation of synapses ensures the proper wiring and function of nervous systems. Specific synapse formation is controlled by synaptic adhesion molecules, which link pre- and post-synaptic cells. Despite this central role, details of how adhesion molecules organize and signal intracellularly to build core synaptic structures are limited. Here, we identify multiple tyrosine phosphorylation sites on the cytoplasmic tail of the C. elegans SYG-1 synaptic adhesion molecule that are critical to initiate presynapse formation. We determine that SRC-1 and SRC-2 tyrosine kinases are redundantly responsible for SYG-1 phosphorylation and are consequently critical for presynapse assembly. The phosphorylated population of SYG-1 localizes in clusters within a larger SYG-1 pool and these clusters mark sites of presynaptic active zone assembly. Reconstitution of SYG-1 clusters in vitro with SH2-domain adapters and WSP-1 reveals a dynamic biomolecular condensate-forming system. Blocking phosphotyrosine adapters and condensate formation in vivo results in the loss of SYG-1 clusters, defective presynapse formation, and compromised neurotransmission. We conclude that phosphorylation of a subpopulation of synaptic adhesion molecules activates and organizes them into condensate-based clusters to initiate presynapse formation.
ER -