SNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling.

Chad W Sauvola,J Troy Littleton

doi:10.3389/fnmol.2021.733138

Abstract

Membrane fusion is a universal feature of eukaryotic protein trafficking and is mediated by the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SNARE proteins embedded in opposing membranes spontaneously assemble to drive membrane fusion and cargo exchange in vitro. Evolution has generated a diverse complement of SNARE regulatory proteins (SRPs) that ensure membrane fusion occurs at the right time and place in vivo. While a core set of SNAREs and SRPs are common to all eukaryotic cells, a specialized set of SRPs within neurons confer additional regulation to synaptic vesicle (SV) fusion. Neuronal communication is characterized by precise spatial and temporal control of SNARE dynamics within presynaptic subdomains specialized for neurotransmitter release. Action potential-elicited Ca2+ influx at these release sites triggers zippering of SNAREs embedded in the SV and plasma membrane to drive bilayer fusion and release of neurotransmitters that activate downstream targets. Here we discuss current models for how SRPs regulate SNARE dynamics and presynaptic output, emphasizing invertebrate genetic findings that advanced our understanding of SRP regulation of SV cycling.

Highlights

Eukaryotes rely on membrane-bound organelles to organize and transport material between cellular compartments (Wickner and Schekman, 2008)
Genetic approaches in Drosophila and C. elegans indicate an essential role for Syntaxin 1 (Syx1) in all forms of synaptic vesicle (SV) fusion, with spontaneous release persisting in the absence of Syb2 and soluble NSF attachment proteins (SNAPs)-25 likely due to compensation from non-SV sensitive factor attachment protein receptor (SNARE)
SNARE regulatory proteins (SRPs) guide SNARE interactions during multiple steps of the SV fusion cycle by localizing SNARE assembly, regulating Ca2+-dependent SNARE zippering, recycling SNAREs postfusion and inhibiting dysregulated SV priming (Figure 7). Given their critical roles in synaptic communication, it is not surprising that mutations in these genes cause a host of severe human neurological disorders (Melom and Littleton, 2011; Engel et al, 2016; Lipstein et al, 2017; Redler et al, 2017; Salpietro et al, 2019; Abramov et al, 2021; Melland et al, 2021)

Summary

Introduction

Eukaryotes rely on membrane-bound organelles to organize and transport material between cellular compartments (Wickner and Schekman, 2008). While the mechanism underlying SNAP-25TS release enhancement is unknown, the T254I mutation in Syx1 has been suggested to enhance release by altering interactions between the fusion clamp Cpx and the SNARE complex (Bykhovskaia et al, 2013), as well as promoting C-terminal domain SNARE zippering (Ma et al, 2015).

Results

Conclusion