Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly

Sundaram, Ramalingam Venkat Kalyana; Jin, Hong; Li, Feng; Shu, Tong; Coleman, Joseph E.; Yang, Jie; Pincet, Frédéric; Zhang, Yongli; Rothman, James E.; Krishnakumar, Shyam S.

doi:10.1002/1873-3468.14006

Cited by 37 publications

(26 citation statements)

References 71 publications

(156 reference statements)

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“…Based on the crystal structure of Vps33, the open form of UNC-18 binds the SNARE domains of synaptobrevin and syntaxin to nucleate SNARE assembly ( Baker et al., 2015 ; Sitarska et al., 2017 ). SNAP-25 is thought to be the last SNARE to enter the complex ( Jiao et al., 2018 ; Kalyana Sundaram et al., 2021 ; Wang et al., 2019 ), although the order is still in dispute ( Lee et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Interspecies complementation identifies a pathway to assemble SNAREs

Parra-Rivas

Palfreyman

et al. 2022

iScience

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Section: Discussionmentioning

confidence: 99%

Interspecies complementation identifies a pathway to assemble SNAREs

Parra-Rivas

Palfreyman

et al. 2022

iScience

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“…In addition to the SNARE motifs of SN25 involved in the formation of the SNARE four helical bundle, other sequences in SN25 have gained attention in recent years. For instance, the linker that connects SN1 and SN2 has been suggested to act as a flexible molecular spacer to ensure efficient S-acylation and support fusion intermediates by local lipid interactions (Salaun et al, 2020; Shaaban et al, 2019), or recruited by Munc13-1 to chaperone SNARE complex assembly (Kalyana Sundaram et al, 2021). In the present study, we identified that the N-peptide sequence (1–10) rather than the SNARE motifs of SN25 mediates interaction with Rph3A FL ( Figure 2 ), and this binding specificity might be conferred by synergistic action of the RBD with the C 2 AB of Rph3A as discussed above.…”

Section: Discussionmentioning

confidence: 99%

Rabphilin 3A binds the N-peptide of SNAP-25 to promote SNARE complex assembly in exocytosis

Cheng

Wang

et al. 2022

Preprint

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Exocytosis of secretory vesicles requires the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and small GTPase Rabs. As a Rab3/Rab27 effector protein on secretory vesicles, Rabphilin 3A was implicated to interact with SNAP-25 to regulate vesicle exocytosis in neurons and neuroendocrine cells, yet the underlying mechanism remains unclear. In this study, we have characterized the physiologically relevant binding sites between Rabphilin 3A and SNAP-25. We found that an intramolecular interplay between the N-terminal Rab-binding domain and C-terminal C2AB domain enables Rabphilin 3A to strongly bind the SNAP-25 N-peptide region via its C2B bottom α-helix. Disruption of this interaction significantly impaired docking and fusion of vesicles with the plasma membrane in PC12 cells. In addition, we found that this interaction allows Rabphilin 3A to accelerate SNARE complex assembly. Furthermore, we revealed that this interaction accelerates SNARE complex assembly via inducing a conformational switch from random coils to α-helical structure in the SNAP-25 SNARE motif. Altogether, our data suggest that promotion of SNARE complex assembly by binding of the C2B bottom α-helix of Rabphilin 3A to the N-peptide of SNAP-25 underlies a pre-fusion function of Rabphilin 3A in vesicle exocytosis.

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“…These other potential sites may interact with Q301/K308 of Munc18-1 domain 3a, which mediates the interaction between MUN and Munc18-1/syntaxin-1 ( Wang et al, 2020 ). Besides, full-length Munc13-1 has additional functions beyond opening the syntaxin-1 linker region, such as membrane tethering and recruiting synaptobrevin-2 and SNAP-25 ( Quade et al, 2019 ; Kalyana Sundaram et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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

Gong

Cui

Qin

et al. 2021

Front. Mol. Neurosci.

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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.

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Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly

Cited by 37 publications

References 71 publications

Interspecies complementation identifies a pathway to assemble SNAREs

Interspecies complementation identifies a pathway to assemble SNAREs

Rabphilin 3A binds the N-peptide of SNAP-25 to promote SNARE complex assembly in exocytosis

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

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