Exploring the Two Coupled Conformational Changes That Activate the Munc18-1/Syntaxin-1 Complex.

Jihong Gong,Ziqi Jin,Cong Ma,Xianping Wang,Yuyang Qin,Xiaofei Yang,Chaoyang Cui

doi:10.3389/fnmol.2021.785696

Abstract

Calcium-dependent synaptic vesicle exocytosis is mediated by SNARE complex formation. The transition from the Munc18-1/syntaxin-1 complex to the SNARE complex is catalyzed by the Munc13-1 MUN domain and involves at least two conformational changes: opening of the syntaxin-1 linker region and extension of Munc18-1 domain 3a. However, the relationship and the action order of the two conformational changes remain not fully understood. Here, our data show that an open conformation in the syntaxin-1 linker region can bypass the requirement of the MUN NF sequence. In addition, an extended state of Munc18-1 domain 3a can compensate the role of the syntaxin-1 RI sequence. Altogether, the current data strongly support our previous notion that opening of the syntaxin-1 linker region by Munc13-1 is a key step to initiate SNARE complex assembly, and consequently, Munc18-1 domain 3a can extend its conformation to serve as a template for association of synaptobrevin-2 and syntaxin-1.

Highlights

Neurotransmitter release is mediated by the calcium-dependent exocytosis of synaptic vesicles (Südhof and Rizo, 2011)
In our previous in vitro studies, we showed that the opening of synatxin-1 linker region and the extension of Munc18-1 domain 3a are driven by the interaction of the Munc13-1 MUN domain with the Munc18-1/syntaxin-1 complex (Wang et al, 2017, 2020)
Previous studies have shown that two conformational changes in the Munc18-1/syntaxin-1 complex are involved in the transition to the SNARE complex, including (i) transition of the linker region of syntaxin-1 from a defined structure to a random coil (Misura et al, 2000; Margittai et al, 2003; Wang et al, 2017)

Summary

Introduction

Neurotransmitter release is mediated by the calcium-dependent exocytosis of synaptic vesicles (Südhof and Rizo, 2011). Synaptic vesicles loaded with neurotransmitters are transported to the presynaptic active zone, docked at the presynaptic membrane, and primed for release in an ATPdependent manner. Upon Ca2+ influx, the vesicles fuse with the presynaptic membrane to release neurotransmitters into the synaptic cleft (Südhof and Rizo, 2011; Jahn and Fasshauer, 2012). The core fusion machinery for synaptic exocytosis comprises three SNAREs (soluble N-ethylmaleimidesensitive-factor-attached protein receptors), including syntaxin-1, synaptobrevin-2, and SNAP-25 (Brunger, 2005; Jahn and Scheller, 2006). To achieve the exact regulation of exocytosis, numbers of other SNARE regulatory proteins are required, including Munc and Munc (Malsam et al, 2008; Jahn and Fasshauer, 2012; Rizo and Xu, 2015)

Methods

Results

Conclusion