ArticleThe Journal of biological chemistry2014
A pivotal role for pro-335 in balancing the dual functions of Munc18-1 domain-3a in regulated exocytosis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- Crotonylation of STXBP1 exacerbates seizure susceptibility by impairing GABAergic synaptic transmission.Cell death and differentiation · 2026Article
- Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F.Human molecular genetics · 2024Article
- Interrogation and validation of the interactome of neuronal Munc18-interacting Mint proteins with AlphaFold2.The Journal of biological chemistry · 2024Article
- Double mutation of open syntaxin and UNC-18 P334A leads to excitatory-inhibitory imbalance and impairs multiple aspects ofbioRxiv : the preprint server for biology · 2023Article
- Article
- SNARE Proteins in Synaptic Vesicle Fusion.Advances in neurobiology · 2023Article
- Functional Roles of UNC-13/Munc13 and UNC-18/Munc18 in Neurotransmission.Advances in neurobiology · 2023Review
- The Role of Tomosyn in the Regulation of Neurotransmitter Release.Advances in neurobiology · 2023Article
- Neuronal SNARE complex assembly guided by Munc18-1 and Munc13-1.FEBS open bio · 2022Review
- Article
- SNARE assembly enlightened by cryo-EM structures of a synaptobrevin-Munc18-1-syntaxin-1 complex.Science advances · 2022Article
- STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies.Journal of neurochemistry · 2021Review
- Exploring the Two Coupled Conformational Changes That Activate the Munc18-1/Syntaxin-1 Complex.Frontiers in molecular neuroscience · 2021Article
- Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.The EMBO journal · 2020Article
- Functional analysis of epilepsy-associated variants in STXBP1/Munc18-1 using humanized Caenorhabditis elegans.Epilepsia · 2020Article
- Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly.Nature communications · 2019Article
- Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones.Nature communications · 2018Article
- Review
- UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Munc18-1 plays essential dual roles in exocytosis: (i) stabilizing and trafficking the central SNARE protein, syntaxin-1 (i.e. chaperoning function), by its domain-1; and (ii) priming/stimulating exocytosis by its domain-3a. Here, we examine whether or not domain-3a also plays a significant role in the chaperoning of syntaxin-1 and, if so, how these dual functions of domain-3a are regulated. We demonstrate that introduction of quintuple mutations (K332E/K333E/P335A/Q336A/Y337L) in domain-3a of Munc18-1 abolishes its ability to bind syntaxin-1 and fails to rescue the level and trafficking of syntaxin-1 as well as to restore exocytosis in Munc18-1/2 double knockdown cells. By contrast, a quadruple mutant (K332E/K333E/Q336A/Y337L) sparing the Pro-335 residue retains all of these capabilities. A single point mutant of P335A reduces the ability to bind syntaxin-1 and rescue syntaxin-1 levels. Nonetheless, it surprisingly outperforms the wild type in the rescue of exocytosis. However, when additional mutations in the neighboring residues are combined with P335A mutation (K332E/K333E/P335A, P335A/Q336A/Y337L), the ability of the Munc18-1 variants to chaperone syntaxin-1 and to rescue exocytosis is strongly impaired. Our results indicate that residues from Lys-332 to Tyr-337 of domain-3a are intimately tied to the chaperoning function of Munc18-1. We also propose that Pro-335 plays a pivotal role in regulating the balance between the dual functions of domain-3a. The hinged conformation of the α-helix containing Pro-335 promotes the syntaxin-1 chaperoning function, whereas the P335A mutation promotes its priming function by facilitating the α-helix to adopt an extended conformation.
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