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

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.

Interspecies complementation identifies a pathway to assemble SNAREs

“…This transition is thought to be mediated by Unc13 proteins (UNC-13/Munc13) ( Gong et al., 2021 ; Hammarlund et al., 2007 ; Ma et al., 2011 ; Magdziarek et al., 2020 ; Richmond et al., 2001 ; Yang et al., 2015 ). Unc18 is required at the final stages to chaperone the SNAREs through their assembly ( André et al., 2020 ; Baker et al., 2015 ; Gong et al., 2021 ; Jiao et al., 2018 ; Lai et al., 2017 ; Rodkey et al., 2008 ; Shu et al., 2020 ; Sitarska et al., 2017 ). The activation steps between open syntaxin and SNARE complex formation are not fully understood.…”