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Multivalent electrostatic pi-cation interaction between synaptophysin and synapsin is responsible for the

Goeun Kim1, Sang-Eun Lee1,2, Seonyoung Jeong1

  • 1Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea.

Molecular Brain
|September 9, 2021
PubMed
Summary

Synaptophysin and synapsin coacervation is driven by pi-cation interactions involving tyrosine residues. This mechanism explains synaptic vesicle clustering and may be regulated during synaptic activity.

Keywords:
Liquid–liquid phase separation (LLPS)Pi–cation interactionsPresynaptic nerve terminalsSynapsinSynaptic vesicle clusterSynaptophysin

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Neuroscience

Background:

  • Synaptophysin (Syph) and synapsin (Syn) induce liquid-liquid phase separation (LLPS) to cluster synaptic vesicles.
  • The mechanism behind Syph and Syn coacervation, despite lacking direct physical interaction, was previously unknown.

Purpose of the Study:

  • To elucidate the underlying mechanism governing the coacervation between synaptophysin and synapsin.
  • To investigate the role of specific molecular interactions in synaptic vesicle clustering.

Main Methods:

  • In vitro and in vivo experiments using intrinsically disordered Syph C-terminal (Ct) domain.
  • Mutagenesis of tyrosine residues in Syph Ct to serine (9YS mutation).
  • Utilizing light-sensitive CRY2PHR or multimeric protein subunits for assisted phase separation in cells.

Main Results:

  • Syph Ct alone can undergo phase separation via self-interactions in a crowding environment or when assisted.
  • Tyrosine residues in Syph Ct are critical for phase separation, as the 9YS mutation abolished this property.
  • The 9YS mutation prevented coacervation with Syn, indicating pi-cation interactions, not just charge, mediate their interaction.

Conclusions:

  • Syph and Syn coacervation is primarily governed by multivalent pi-cation electrostatic interactions between Syph tyrosine residues and positively charged Syn.
  • This finding reveals the molecular basis for synaptic vesicle clustering.
  • Regulation of these pi-cation interactions may play a role in synaptic vesicle dynamics during neuronal activity.