The N-peptide–binding mode is critical to Munc18-1 function in synaptic exocytosis

Shen, Chong; Liu, Yinghui; Yu, Haijia; Gulbranson, Daniel R.; Kogut, Igor; Bilousova, Ganna; Zhang, Chen; Stowell, Michael H. B.; Shen, Jingshi

doi:10.1074/jbc.ra118.005254

Cited by 9 publications

(8 citation statements)

References 66 publications

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“…Despite substantial evidence that SM proteins bind to R-SNAREs (44,(100)(101)(102), only one structure of an SM-R-SNARE complex has been reported: Vps33 bound to the SNARE motif of Nyv1 (27). The R-SNARE binding site, while distinct from the Qa-SNARE binding site, is formed almost entirely by the extended helical hairpin (Figure 2c).…”

Section: Sec1/munc18-r-snare Complexesmentioning

confidence: 99%

Chaperoning SNARE Folding and Assembly

Zhang

Hughson

2021

Annu. Rev. Biochem.

104

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SNARE proteins and Sec1/Munc18 (SM) proteins constitute the core molecular engine that drives nearly all intracellular membrane fusion and exocytosis. While SNAREs are known to couple their folding and assembly to membrane fusion, the physiological pathways of SNARE assembly and the mechanistic roles of SM proteins have long been enigmatic. Here, we review recent advances in understanding the SNARE–SM fusion machinery with an emphasis on biochemical and biophysical studies of proteins that mediate synaptic vesicle fusion. We begin by discussing the energetics, pathways, and kinetics of SNARE folding and assembly in vitro. Then, we describe diverse interactions between SM and SNARE proteins and their potential impact on SNARE assembly in vivo. Recent work provides strong support for the idea that SM proteins function as chaperones, their essential role being to enable fast, accurate SNARE assembly. Finally, we review the evidence that SM proteins collaborate with other SNARE chaperones, especially Munc13-1, and briefly discuss some roles of SNARE and SM protein deficiencies in human disease. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Sec1/munc18-r-snare Complexesmentioning

confidence: 99%

Chaperoning SNARE Folding and Assembly

Zhang

Hughson

2021

Annu. Rev. Biochem.

104

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“…The N‐peptide of syntaxin‐1 binds to domain 1 on the opposite side of the Munc18‐1 cavity (Fig. 1B ), which is crucial for synaptic vesicle exocytosis [ 29 , 30 , 80 ]. This interaction not only assists Munc18‐1 to clamp the closed conformation of syntaxin‐1 [ 78 ] but also enhances binding of Munc18‐1 with the SNARE four‐helical bundle [ 81 , 82 , 83 ].…”

Section: Munc18‐1mentioning

confidence: 99%

Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

Wang

2022

FEBS Open Bio

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Neurotransmitter release by Ca2+‐triggered synaptic vesicle exocytosis is essential for information transmission in the nervous system. The soluble N‐ethylmaleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form the SNARE complex to bring synaptic vesicles and the plasma membranes together and to catalyze membrane fusion. Munc18‐1 and Munc13‐1 regulate synaptic vesicle priming via orchestrating neuronal SNARE complex assembly. In this review, we summarize recent advances toward the functions and molecular mechanisms of Munc18‐1 and Munc13‐1 in guiding neuronal SNARE complex assembly, and discuss the functional similarities and differences between Munc18‐1 and Munc13‐1 in neurons and their homologs in other intracellular membrane trafficking systems.

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“…So far, the physiological roles of STX1’s N-peptide, H abc -domain, and open-closed conformation were not assessed in central synapses completely devoid of STX1. Rather, studies have been conducted either in synapses with normal STX1 expression but mutant Munc18-1 ( Khvotchev et al, 2007 ; Meijer et al, 2012 ; Shen et al, 2018 ) or in synapses with only severely reduced expression of STX1 ( Zhou et al, 2013 ). Furthermore, in vitro studies do not contain the full panel of native synaptic proteins and mostly do not use full-length STX1 ( Shen et al, 2007 ; Rathore et al, 2010 ; Shen et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Reexamination of N-terminal domains of syntaxin-1 in vesicle fusion from central murine synapses

Vardar

Salazar-Lázaro

Brockmann

et al. 2021

eLife

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Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open-conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

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The N-peptide–binding mode is critical to Munc18-1 function in synaptic exocytosis

Cited by 9 publications

References 66 publications

Chaperoning SNARE Folding and Assembly

Chaperoning SNARE Folding and Assembly

Neuronal SNARE complex assembly guided by Munc18‐1 and Munc13‐1

Reexamination of N-terminal domains of syntaxin-1 in vesicle fusion from central murine synapses

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