Affinage

UNC13A

Protein unc-13 homolog A · UniProt Q9UPW8

Length
1703 aa
Mass
193.0 kDa
Annotated
2026-06-10
92 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UNC13A/Munc13-1 is an essential presynaptic active zone protein that primes synaptic vesicles to a fusion-competent state, a function required for evoked neurotransmitter release at glutamatergic synapses (PMID:10440375). It executes priming by directly engaging the SNARE machinery: it binds syntaxin-1 and facilitates its opening from the autoinhibited state through weak but functionally critical contacts with the syntaxin-1 linker, an active role that cannot be substituted by a passive tethering factor (PMID:8999968, PMID:32086964). Its elongated C1C2BMUNC2C module physically bridges the synaptic vesicle and plasma membranes—with the C2C domain contacting the vesicle membrane and a polybasic C1-C2B face controlling priming—so that point mutations in these surfaces disrupt liposome bridging, vesicle docking, and Ca2+-triggered release (PMID:30816091, PMID:34779770). The MUN domain chaperones SNARE assembly by stabilizing the Munc18-1/syntaxin-1/VAMP2 template complex and clustering SNARE complexes to synchronize release (PMID:31888993, PMID:38755165). Munc13-1 is a convergence point for multiple regulatory inputs: diacylglycerol/phorbol ester acting through its C1 domain lowers the energy barrier for fusion and mediates Gq/PLC-coupled potentiation (PMID:17267576, PMID:17202488), while Ca2+/calmodulin and Ca2+/phospholipid binding through the CaM-binding and C2B domains accelerate vesicle replenishment and control short-term plasticity (PMID:23770256, PMID:34706220). Its activity is held in check by intramolecular autoinhibition, in which the N-terminal C2A, CaM-binding, and acidic polyE segments engage the MUN domain to suppress SNARE assembly; this is relieved by RIM zinc-finger binding, calmodulin, and Ca2+ (PMID:38417672, PMID:40489622). Munc13-1 is recruited to and stabilized at the active zone through RIM1α binding and forms supramolecular self-assemblies that define independent release sites and thereby set synaptic weight (PMID:16704978, PMID:29230050). Beyond neurons, Munc13-1 primes insulin granules and is required for glucose-stimulated insulin secretion (PMID:16644700, PMID:16697276). Germline coding and splice-site UNC13A variants cause a neurodevelopmental syndrome through reduced expression, gain-of-function increases in neurotransmission, or impaired second-messenger regulation (PMID:28192369, PMID:41125872), and nuclear loss of TDP-43 de-represses a cryptic exon in UNC13A pre-mRNA that triggers nonsense-mediated decay and protein depletion, mechanistically linking TDP-43 proteinopathy in ALS/FTD to synaptic failure (PMID:35197626, PMID:35197628).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 High

    Established the first molecular link between Munc13-1 and the fusion machinery by showing it physically engages syntaxin-1 and the SNARE core complex, raising the question of how it intersects Munc18 function.

    Evidence Yeast two-hybrid, GST pulldown, and co-immunoprecipitation mapping the C-terminal syntaxin-binding site

    PMID:8999968

    Open questions at the time
    • Functional consequence of syntaxin binding not yet shown
    • Mechanism of competition with Munc18 not resolved
  2. 1998 High

    Defined Munc13-1 as a high-affinity DAG/phorbol ester receptor whose membrane translocation enhances release, identifying it as a presynaptic second-messenger effector.

    Evidence Radioligand binding, membrane translocation imaging, and Xenopus NMJ overexpression electrophysiology

    PMID:9697857

    Open questions at the time
    • Endogenous role versus overexpression artifact not yet distinguished
    • Structural basis of the C1-membrane interaction unknown
  3. 1999 High

    Demonstrated that Munc13-1 is essential and acts specifically at the vesicle priming step, since knockout neurons form normal synapses but cannot release transmitter.

    Evidence Munc13-1 knockout mice with electrophysiology across multiple release stimuli and electron microscopy

    PMID:10440375

    Open questions at the time
    • Transmitter-specific (glutamate vs GABA) basis not explained molecularly
    • Biochemical mechanism of priming not defined
  4. 2001 High

    Placed Munc13-1 in the active zone protein network by showing its RIM1 interaction is required for generating fusion-competent vesicles, separating priming from RIM binding into distinct modules.

    Evidence Co-immunoprecipitation, dominant-negative disruption, and electrophysiology in cultured neurons

    PMID:11343654

    Open questions at the time
    • Whether RIM binding controls localization vs activity unresolved at this stage
  5. 2002 Medium

    Expanded the active zone scaffold to a ternary CAST/RIM1/Munc13-1 complex, integrating Munc13-1 into the cytomatrix.

    Evidence Co-immunoprecipitation, yeast two-hybrid, and immunolocalization

    PMID:12163476

    Open questions at the time
    • Munc13-1 interaction is indirect via RIM1
    • Functional role of CAST for Munc13-1 not tested
  6. 2005 High

    Localized the minimal priming activity to the C-terminal C1C2BMUNC2C region and proved that syntaxin binding is required for priming function.

    Evidence Deletion constructs and point mutagenesis in a chromaffin cell capacitance gain-of-function assay; NMR structure of the C1 domain

    PMID:15667202 PMID:16271475

    Open questions at the time
    • How the C1 Trp-588 occlusion is relieved in vivo unknown
    • Full-length structure not available
  7. 2006 High

    Resolved a C2A homodimer-to-RIM-heterodimer switch and established that RIM1α binding recruits Munc13-1 to the active zone, connecting localization to plasticity.

    Evidence Crystal structures of C2A homo- and heterodimers; point mutagenesis (I121N) plus RIM1α knockout mice and localization assays

    PMID:16704978 PMID:16732694

    Open questions at the time
    • In vivo trigger of the dimer switch not demonstrated
    • Quantitative contribution of recruitment vs activation unclear
  8. 2006 High

    Generalized Munc13-1 priming function beyond neurons by showing it is required for glucose-stimulated and sustained-phase insulin secretion in pancreatic beta cells.

    Evidence Munc13-1 knockout and H567K knockin mice, glucose tolerance tests, beta-cell patch-clamp and secretion assays

    PMID:16644700 PMID:16697276

    Open questions at the time
    • Whether the same SNARE-priming mechanism operates on LDCVs as on SVs not directly compared
  9. 2007 High

    Defined a two-state DAG/C1 regulatory model in which C1 activation lowers the fusion energy barrier without altering pool size, and identified Munc13-1 as the PLC effector for receptor-driven potentiation.

    Evidence Munc13-1-H567K knockin mice with multiple electrophysiological assays; chromaffin cell pharmacological dissection of Gq/PLC signaling

    PMID:17202488 PMID:17267576

    Open questions at the time
    • Structural basis of the C1 conformational switch in situ not shown
    • Chromaffin pathway study is dominant-negative based
  10. 2009 Medium

    Mapped a convergence node on the Munc13-1 N-terminus where multiple active zone scaffold proteins bind, framing Munc13-1 as an organizing hub.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and recombinant domain binding assays

    PMID:19812333

    Open questions at the time
    • Most pairwise interactions are single-method
    • Functional hierarchy of these interactions untested
  11. 2013 High

    Identified Ca2+/calmodulin acting through the CaM-binding domain as the molecular controller of vesicle replenishment and short-term plasticity, and characterized Doc2B/Ca2+-dependent and β-adrenergic/cAMP-Epac-PLC recruitment of Munc13-1 to membranes.

    Evidence Munc13-1-W464R knockin mice at calyx of Held; live-cell imaging in PC12 cells; synaptosome fractionation, co-IP, glutamate release and EM

    PMID:23770256 PMID:24036110 PMID:24062723

    Open questions at the time
    • Doc2B and β-adrenergic findings are single-lab
    • Integration of multiple signaling inputs at one molecule not quantitatively modeled
  12. 2011 Medium

    Linked RIM1α-Munc13-1 binding to presynaptic long-term potentiation, identifying vesicle-priming modulation as a cellular substrate for LTP.

    Evidence In vivo viral expression of RIM-binding-deficient Munc13-1 mutants with mossy fiber electrophysiology

    PMID:21849565

    Open questions at the time
    • Single lab
    • Molecular event downstream of RIM binding during LTP not defined
  13. 2017 High

    Connected Munc13-1 dysfunction to human disease by showing a de novo P814L gain-of-function variant increases fusion propensity and disrupts plasticity, and resolved Munc13-1 self-assemblies as independent release sites that set synaptic weight.

    Evidence Variant electrophysiology in mouse neurons and C. elegans; super-resolution imaging with single-synapse glutamate measurements

    PMID:28192369 PMID:29230050

    Open questions at the time
    • Molecular basis of the supramolecular assembly not structurally defined
    • Link between assembly number and release-site count mechanistically incomplete
  14. 2019 High

    Provided a unified membrane-bridging and SNARE-chaperoning mechanism, showing the C2C domain bridges vesicle and plasma membranes while the MUN domain stabilizes the Munc18-1 template complex to drive SNARE assembly.

    Evidence Liposome bridging/fusion reconstitution, single-molecule force spectroscopy, mutagenesis, neuronal electrophysiology and EM; RIM-BP2 knockout mice

    PMID:30816091 PMID:31535974 PMID:31888993

    Open questions at the time
    • How bridging and chaperoning are temporally coordinated unresolved
    • Synapse-type specificity of RIM-BP2 effect not mechanistically explained
  15. 2020 High

    Demonstrated that Munc13-1 actively opens syntaxin-1 via weak linker-region binding rather than the SNARE motif, establishing a catalytic role beyond passive tethering.

    Evidence NMR, SNARE assembly assays, and liposome fusion reconstitution with mutagenesis

    PMID:32086964

    Open questions at the time
    • Structural snapshot of the open-syntaxin intermediate lacking
    • Kinetics of opening in the full active zone context unknown
  16. 2021 High

    Dissected Munc13-1 membrane-binding surfaces and clustering requirements, separating the polybasic priming face from the DAG/Ca2+/PIP2 release-modulating face and showing ≥6-copy clusters are needed for vesicle capture.

    Evidence Supported-lipid-bilayer reconstitution with TIRF and photobleaching; point mutagenesis with liposome assays and neuronal electrophysiology; C2B Ca2+/phospholipid knockin mice at calyx of Held

    PMID:34227103 PMID:34706220 PMID:34779770

    Open questions at the time
    • Physiological trigger of clustering in vivo not established
    • How distinct membrane faces are coordinated during a release cycle unclear
  17. 2022 High

    Revealed the disease-driving regulatory axis: nuclear TDP-43 loss de-represses a UNC13A cryptic exon causing NMD and protein depletion, potentiated by ALS/FTD-risk SNPs overlapping TDP-43 binding sites.

    Evidence TDP-43 knockdown in human neuronal lines and iPSC motor neurons, RT-PCR, minigene splicing, RNA-seq, NMD assays, and postmortem ALS/FTD tissue; replicated by two concurrent studies

    PMID:35197626 PMID:35197628

    Open questions at the time
    • Quantitative contribution of UNC13A loss to ALS/FTD pathophysiology not yet established
    • Whether partial protein loss alone causes neurodegeneration unresolved
  18. 2023 Medium

    Broadened the splicing-control network and refined the calmodulin-priming model, identifying TDP-43's N-terminus and hnRNP L/A1/A2B1 as cryptic-exon repressors and showing CaM-domain control of vesicle stabilization and homeostatic plasticity.

    Evidence TDP-43 domain-deletion and RIP assays with patient brain correlation; Drosophila NMJ electrophysiology, STED microscopy, and mathematical modeling of CaM-domain mutants

    PMID:36930682 PMID:37243591

    Open questions at the time
    • hnRNP findings are single-lab
    • How multiple RBPs cooperate on the cryptic exon not resolved
  19. 2024 High

    Established intramolecular autoinhibition as a core regulatory principle, showing N-terminal C2A/CaMb/polyE segments suppress MUN-driven SNARE assembly until relieved by RIM, calmodulin, or local Ca2+, and resolved how Munc13-1 vs Munc18-1 differentially chaperone SNAREs to control fusion pores; ASO rescue confirmed cryptic-exon causality.

    Evidence Near-full-length Munc13-1 purification with liposome fusion and NMR; biochemical/electrophysiological dissection of polyE-MUN-Ca2+ competition; single-molecule fusion-pore assays; ASO rescue of TDP-43-depleted neurons on multi-electrode arrays (preprint)

    PMID:38417672 PMID:38755165 PMID:38979232 PMID:40489622

    Open questions at the time
    • How autoinhibitory inputs are integrated quantitatively in vivo unresolved
    • ASO rescue is preprint and not yet in vivo
  20. 2025 High

    Consolidated UNC13A as a Mendelian neurodevelopmental disease gene with three distinct variant mechanisms and identified an upstream transcriptional control axis through ALS-RBP-mediated REST regulation.

    Evidence Variant expression in mouse hippocampal neurons and C. elegans with genotype-phenotype correlation; RBP knockdowns, RIP, and patient iPSC motor neurons linking MATR3/FUS/hnRNPA1-REST to UNC13A transcription

    PMID:40707625 PMID:41125872

    Open questions at the time
    • REST-axis study is single-lab
    • Relative contribution of transcriptional vs splicing regulation to disease in patients not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, overlapping regulatory inputs (DAG/C1, Ca2+/calmodulin, Ca2+/phospholipid, RIM, polyE autoinhibition, clustering) are integrated in real time at a single active zone to set release probability and plasticity remains unresolved.
  • No integrated structural model of full-length Munc13-1 in the active zone
  • Temporal coordination of autoinhibition relief with Ca2+ influx during an action potential not directly observed
  • Therapeutic correction of UNC13A loss not validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0140299 molecular sensor activity 4 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 2
Partners
CALM1DOC2BERC1/CASTRIMBP2RIMS1STX1AUNC18-1/STXBP1VAMP2
Complex memberships
Munc13-1 supramolecular release-site assemblyMunc18-1/syntaxin-1/VAMP2 template complexactive zone cytomatrix (CAST/RIM1/Munc13-1/Bassoon)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Munc13-1 directly interacts with the N-terminal coiled-coil domain of syntaxin-1 via its C-terminus, demonstrated by three independent methods (in vitro binding, yeast two-hybrid, co-immunoprecipitation). Through this interaction, Munc13-1 binds a subpopulation of the SNARE core complex (synaptobrevin/SNAP-25/syntaxin). The syntaxin-binding site overlaps with that of Munc18, suggesting competition for syntaxin binding. Yeast two-hybrid, GST pulldown, co-immunoprecipitation The Journal of biological chemistry High 8999968
1998 Munc13-1 is a high-affinity presynaptic phorbol ester and diacylglycerol receptor with ligand affinities similar to protein kinase C. Phorbol ester binding causes Munc13-1 to associate with the plasma membrane, and overexpression of Munc13-1 presynaptically in the Xenopus neuromuscular junction enhances transmitter release in a phorbol ester-dependent manner. Radioligand binding assay, immunofluorescence membrane translocation, Xenopus NMJ electrophysiology overexpression Neuron High 9697857
1999 Munc13-1 is essential for synaptic vesicle maturation (priming) to a fusion-competent state at glutamatergic synapses. Hippocampal neurons from Munc13-1 knockout mice form ultrastructurally normal synapses but cannot release transmitter in response to action potentials, Ca2+-ionophores, or hypertonic sucrose, while α-latrotoxin-evoked release is unaffected. GABAergic synapses are unaffected, demonstrating transmitter-specific priming mechanisms. Munc13-1 knockout mice, electrophysiology, electron microscopy Nature High 10440375
2001 Munc13-1 functionally interacts with the active zone protein RIM1 (a Rab3 effector). Disruption of the Munc13-1/RIM1 interaction causes loss of fusion-competent synaptic vesicles, phenocopying Munc13-1-deficient neurons. RIM1 binding and vesicle priming are mediated by two distinct structural modules of Munc13-1. Co-immunoprecipitation, dominant-negative disruption, electrophysiology in cultured neurons Neuron High 11343654
2002 CAST (CAZ-associated structural protein) forms a ternary complex with RIM1 and Munc13-1 at the cytomatrix of the active zone. CAST binds RIM1 directly and Munc13-1 indirectly through RIM1, and Bassoon is also associated with this complex. Co-immunoprecipitation, yeast two-hybrid, immunolocalization The Journal of cell biology Medium 12163476
2005 The minimal priming domain of Munc13-1 resides in its C-terminal residues 1100–1735, which contains both Munc13 homology domains and the C-terminal C2 domain. Point mutations that abolish syntaxin-1 binding also abolish chromaffin granule priming activity, establishing that Munc13-1's interaction with syntaxin-1 is required for its priming function. Munc13-1 deletion constructs in electrophysiological gain-of-function assay (chromaffin cell capacitance), point mutagenesis Current biology : CB High 16271475
2005 NMR structure of the Munc13-1 C1 domain reveals that a conserved tryptophan (Trp-588) occludes the DAG/phorbol ester binding site, requiring a conformational change for ligand binding. This structural feature distinguishes Munc13-1 from PKC C1 domains and is predicted to require higher DAG levels for activation. NMR spectroscopy (3D structure determination) Biochemistry High 15667202
2006 Crystal structures of the Munc13-1 C2A domain homodimer (1.44 Å) and the Munc13-1 C2A/RIM zinc-finger domain heterodimer (1.78 Å) reveal that homodimerization (via four-stranded concave face) and heterodimerization (via bottom tip and C-terminal helix) are mutually exclusive, suggesting a homodimer-to-heterodimer switch that may regulate vesicle priming and presynaptic plasticity. X-ray crystallography guided by NMR experiments PLoS biology High 16732694
2006 Active zone recruitment of Munc13-1 and ubMunc13-2 depends on their binding to RIM1α. A single point mutation (I121N) abolishes RIM1α binding in vitro and in cells; RIM1α-binding-deficient ubMunc13-2(I121N) is not recruited to synapses. Munc13-1 levels are reduced and improperly enriched at active zones in RIM1α-deficient brains. Mutagenesis, co-immunoprecipitation, immunofluorescence in cultured neurons and brain sections, RIM1α knockout mice The Journal of biological chemistry High 16704978
2007 Activation of the Munc13-1 C1 domain by phorbol ester (PDBu) lowers the energy barrier for synaptic vesicle fusion without changing the size of the readily releasable pool. The C1 domain mutation H567K (PDBu-binding deficient) mimics the PDBu-activated state, acting as a constitutive gain-of-function that increases vesicular release rate. This defines a two-state regulatory model analogous to PKC. Knockin mice (Munc13-1-H567K), osmotic release, Ca2+-triggered and spontaneous release electrophysiology The Journal of neuroscience High 17267576
2007 Munc13-1 is required for Gq-coupled receptor (histamine H1 receptor) potentiation of exocytosis via PLC/DAG signaling in chromaffin cells. The DAG-insensitive Munc13-1(H567K) completely abolished histamine-induced potentiation, while PKC inhibition had no effect, establishing that Munc13-1 is the downstream effector of PLC for rapid exocytotic potentiation. Adenoviral overexpression, capacitance measurements, pharmacological dissection The Journal of neuroscience Medium 17202488
2006 Munc13-1 is expressed in pancreatic islet beta cells and is required for glucose-stimulated insulin secretion. Heterozygous Munc13-1 (+/-) knockout mice show reduced insulin secretion, impaired granule priming (reduced readily releasable pool and refilling), and abnormal glucose tolerance. The DAG-binding function of Munc13-1 contributes to phorbol ester-dependent potentiation of insulin secretion. Munc13-1 knockout and H567K knockin mice, intraperitoneal glucose tolerance test, patch-clamp capacitance measurements on beta cells Diabetes High 16644700
2006 Munc13-1 is required for the sustained (second phase) insulin release from pancreatic beta cells upon prolonged stimulation. Munc13-1 knockout eliminates the second phase of insulin secretion, and the DAG-binding-deficient H567K knockin also reduces it, demonstrating DAG-dependent priming of insulin-containing LDCVs. Munc13-1 knockout and H567K knockin mice, insulin secretion assay from primary beta cells Cell metabolism High 16697276
2009 Domains of five active zone proteins (Aczonin/Piccolo, Bassoon, CAST1/ELKS2, RIM1, and Munc13-1) converge on an interaction node centered on the N-terminal region of Munc13-1. The zinc-finger domain of RIM1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the CC3 domain of Aczonin/Piccolo all bind the Munc13-1 N-terminal region. Yeast two-hybrid, co-immunoprecipitation, recombinant domain binding assays The Journal of neuroscience Medium 19812333
2011 The interaction between RIM1α and Munc13-1 is required for presynaptic long-term potentiation (LTP) at hippocampal mossy fiber synapses. Using acute in vivo expression of Munc13-1 variants in which the RIM-binding domain is selectively disrupted, Munc13-1 was shown to be an effector of RIM1α in presynaptic LTP, implicating modulation of vesicle priming as the cellular substrate for LTP expression. In vivo viral expression of Munc13-1 domain mutants, electrophysiology at hippocampal mossy fiber synapses The Journal of neuroscience Medium 21849565
2013 Munc13-1 is a major presynaptic target of Ca2+/calmodulin signaling that controls synaptic vesicle replenishment and short-term plasticity. Knockin mice expressing a Ca2+/calmodulin-insensitive Munc13-1(W464R) variant show slower SV replenishment, aberrant short-term depression, and reduced recovery from synaptic depression at the calyx of Held. Knockin mice (Munc13-1-W464R), electrophysiology at calyx of Held Neuron High 23770256
2013 Munc13-1 translocates to the plasma membrane in a Doc2B- and calcium-dependent manner. When co-expressed with Doc2B, Munc13-1 co-translocates upon Ca2+ elevation but at a slower rate, and accumulates on the membrane after stimulation in a DAG-dependent manner (abrogated by H567K mutation). Doc2B thus enables a Ca2+- and DAG-dependent recruitment of Munc13-1 to the plasma membrane. Live-cell fluorescence imaging of GFP-tagged proteins in PC12 cells, Ca2+ stimulation Frontiers in endocrinology Medium 24062723
2013 β-adrenergic receptor activation translocates Munc13-1 from soluble to particulate (membrane) fractions via a cAMP/Epac/PLC/DAG pathway and enhances the Rab3A–RIM1α interaction, redistributing synaptic vesicles closer to the presynaptic membrane and increasing glutamate release at cerebrocortical terminals. Subcellular fractionation, co-immunoprecipitation, glutamate release assay from synaptosomes, electron microscopy The Journal of biological chemistry Medium 24036110
2017 A de novo Pro814Leu variant in UNC13A (Munc13-1) causes a dominant gain-of-function characterized by increased synaptic vesicle fusion propensity, increased initial release probability, and abnormal short-term synaptic plasticity. This was demonstrated in murine neuronal cultures and in C. elegans expressing the variant. Electrophysiology in murine neuronal cultures, C. elegans functional assays, whole-exome sequencing The Journal of clinical investigation High 28192369
2017 Munc13-1 forms discrete supramolecular self-assemblies in presynaptic terminals that serve as independent vesicular release sites by recruiting syntaxin-1. The multiplicity of these assemblies sets synaptic weight, with each assembly functioning as an independent release site. Single-synapse glutamate imaging, super-resolution (STORM/PALM) microscopy, correlative functional and structural analysis Nature neuroscience High 29230050
2018 TNF-α impedes Fbxo45-dependent ubiquitination of Munc13-1 in the spinal dorsal horn, causing Munc13-1 accumulation at presynaptic sites. Neuropathic injury decreases Fbxo45 expression and Fbxo45–Munc13-1 co-precipitation, increasing mEPSC frequency. Spinal Munc13-1 knockdown attenuates allodynia, establishing Fbxo45 as the E3 ubiquitin ligase targeting Munc13-1 for degradation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, patch-clamp electrophysiology, behavioral testing in rats Cell death & disease Medium 30042425
2019 Munc13-1 bridges the synaptic vesicle and plasma membranes through its elongated C1C2BMUNC2C region. Mutations in membrane-binding sites of the C2C domain disrupt liposome bridging, liposome fusion in vitro, and synaptic vesicle docking, priming, and Ca2+-triggered neurotransmitter release in mouse neurons, with a single residue substitution nearly abolishing release. Liposome bridging and fusion assays, mutagenesis, electrophysiology in mouse neurons, electron microscopy (vesicle docking) eLife High 30816091
2019 The MUN domain of Munc13-1 stabilizes the Munc18-1/syntaxin-1/VAMP2 template complex by ~2.1 kBT, as measured by single-molecule force spectroscopy. The MUN-bound template complex enhances SNAP-25 binding and promotes full SNARE assembly. Mutational studies confirm functional importance for SNARE assembly and neurotransmitter release. Single-molecule force spectroscopy, SNARE assembly assays, mutagenesis Proceedings of the National Academy of Sciences High 31888993
2019 RIM-BP2 promotes synaptic vesicle priming and release probability at hippocampal mossy fiber synapses via stabilization of Munc13-1 at the active zone. At CA3-CA1 synapses, RIM-BP2 loss only affects Ca2+-secretion coupling without affecting Munc13-1-dependent priming, demonstrating synapse type-specific RIM-BP2/Munc13-1 functional interactions. RIM-BP2 knockout mice, electrophysiology at two synapse types, immunostaining/quantification of Munc13-1 levels eLife Medium 31535974
2020 NMR spectroscopy, SNARE complex assembly experiments, and liposome fusion assays demonstrate that Munc13-1 facilitates opening of syntaxin-1 via interactions with the syntaxin-1 linker region (very weak binding but functionally critical) rather than via the syntaxin-1 SNARE motif. Munc13-1 cannot be replaced by an artificial tethering factor for liposome fusion, indicating it has an active role beyond membrane bridging. NMR spectroscopy, SNARE complex assembly assays, liposome fusion reconstitution, mutagenesis Protein science High 32086964
2021 Munc13-1 must self-assemble into clusters on supported lipid bilayers to efficiently capture and retain synaptic vesicles. Purified Munc13-1 forms clusters of 2–20 copies, but only clusters of ≥6 copies efficiently capture vesicles. The C2C domain is not required for clustering but is required for efficient vesicle capture via electrostatic and hydrophobic interactions. Reconstitution on supported lipid bilayers, TIRF microscopy, stepwise photobleaching, domain deletion analysis FEBS letters Medium 34227103
2021 The C1-C2B region of Munc13-1 has two distinct membrane-binding faces. Mutations in the polybasic face (K603E, R769E) severely impair Ca2+-independent liposome bridging/fusion and synaptic vesicle priming. A K706E mutation in the C2B Ca2+-binding loops impairs Ca2+-evoked release. The polybasic face primarily controls vesicle priming while the DAG/Ca2+/PIP2-binding face modulates Ca2+-evoked release. In vitro liposome bridging/fusion reconstitution, point mutagenesis, electrophysiology in murine hippocampal cultures eLife High 34779770
2021 Munc13-1 regulates synaptic vesicle replenishment via Ca2+/phospholipid-dependent binding through its C2B domain. Knockin mice with mutations abolishing Ca2+/phospholipid binding show increased synaptic depression and slower SV pool recovery; mutations enhancing binding have opposite effects. This identifies Ca2+/phospholipid binding to Munc13-1 C2B as a core mechanism accelerating SV resupply. Knockin mice with C2B domain point mutations, electrophysiology at calyx of Held Neuron High 34706220
2022 TDP-43 represses a cryptic exon in UNC13A pre-mRNA. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines, and iPSC-derived motor neurons results in inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. Risk SNPs for FTD/ALS located within the intron containing the cryptic exon increase cryptic exon inclusion in the context of TDP-43 dysfunction. TDP-43 knockdown in human neuronal cell lines and iPSC-derived motor neurons, RT-PCR, Western blot, RNA-seq, postmortem human brain analysis Nature High 35197626 35197628
2022 TDP-43 depletion induces robust cryptic exon inclusion in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms (rs12608932 and rs12973192) associated with ALS/FTD risk overlap with TDP-43 binding sites and potentiate cryptic exon inclusion both in cultured cells and in patient brain/spinal cord. TDP-43 knockdown, RT-PCR, minigene splicing assays, postmortem ALS/FTD patient brain and spinal cord analysis, cell-based NMD assays Nature High 35197628
2022 Paramagnetic NMR (pseudocontact shifts and residual dipolar couplings) of the Calmodulin/Munc13-1 complex reveals highly flexible interdomain motion. A genetic algorithm ensemble approach characterized the conformational space of the CaM/Munc13-1 complex without prior crystallographic knowledge. Paramagnetic NMR spectroscopy (pseudocontact shifts, residual dipolar couplings), molecular mechanics ensemble calculation Journal of the American Chemical Society Medium 36082939
2023 TDP-43's extreme N-terminus is important for repression of UNC13A cryptic exon inclusion. Additionally, hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion independently of TDP-43. Higher hnRNP L protein levels associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. TDP-43 domain-deletion constructs, RNA immunoprecipitation, minigene splicing assays, patient brain correlative analysis PLoS biology Medium 36930682
2024 The N-terminal C2A and CaM-binding (CaMb) domains of Munc13-1 interact with its own MUN domain (intramolecular autoinhibition), suppressing SNARE complex assembly and liposome fusion activity. These inhibitory interactions are relieved by RIM2α zinc-finger domain (relieving C2A-MUN interaction) and calmodulin (relieving CaMb-MUN interaction), providing a mechanism for dual regulation of Munc13-1 activity. Purification of full-length Munc13-1 fragment, liposome fusion assays, NMR spectroscopy Journal of molecular biology High 38417672
2024 TDP-43 loss of function induces severe reduction in synaptic transmission and asynchronous network activity. These deficits are largely driven by a cryptic exon in UNC13A. Antisense oligonucleotides (ASOs) targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function. TDP-43 depletion in neuronal cultures, multi-electrode array recordings, ASO treatment, Western blot bioRxivpreprint Medium 38979232
2024 Differential SNARE chaperoning by Munc13-1 and Munc18-1 regulates fusion pore fate. Munc13-1 clusters multiple SNARE complexes at the release site and synchronizes release events, while Munc18-1 stoichiometrically interacts with trans-SNARE complexes to enhance N-to-C-terminal zippering. Together, both proteins differentially access dynamic trans-SNARE complexes to regulate pore properties. Single-molecule fusion pore assay, SNARE reconstitution, fluorescence imaging Nature communications High 38755165
2024 A negatively charged polyE sequence in the N-terminus of Munc13-1 binds the MUN domain via charge-charge interactions, inhibiting MUN-mediated SNARE complex assembly. Ca2+ ions (~40 μM, comparable to local presynaptic Ca2+ from a single action potential) compete with the polyE-MUN interaction to relieve autoinhibition and enhance neurotransmitter release. Pseudophosphorylated mutations in the MUN domain that disrupt polyE binding enhance release. In vitro binding assays, SNARE assembly assays, mutagenesis (pseudophosphorylation), electrophysiology in neurons Proceedings of the National Academy of Sciences High 40489622
2025 Pathogenic germline coding or splice-site UNC13A variants cause a neurodevelopmental syndrome through three distinct mechanisms: (1) reduced UNC13A protein expression causing loss of synaptic strength, (2) gain-of-function UNC13A variants causing increased neurotransmission, and (3) impaired regulation of neurotransmission by second messenger signaling. These mechanisms were validated in mouse hippocampal neurons and C. elegans. Variant expression in mouse hippocampal neurons, C. elegans functional assays, electrophysiology, genotype-phenotype correlation Nature genetics High 41125872
2025 ALS-associated RNA-binding proteins MATR3, FUS, and hnRNPA1 promote UNC13A transcription by binding to and downregulating REST mRNA, thereby relieving REST-mediated transcriptional repression of UNC13A. Loss of these RBPs in cultured cells or ALS patient motor neurons leads to REST overexpression and reduced UNC13A levels. siRNA knockdown, RT-PCR, Western blot, RNA immunoprecipitation, iPSC-derived motor neurons from ALS patients The EMBO journal Medium 40707625
2023 Unc13A's calmodulin-binding (CaM) domain mutation in Drosophila increases baseline transmission while blocking both short-term facilitation and presynaptic homeostatic potentiation. Mathematical modeling suggests Ca2+/calmodulin/Unc13A interaction plastically stabilizes vesicle priming at release sites, and CaM-domain mutation causes constitutive stabilization, occluding activity-dependent plasticity. STED microscopy shows CaM-domain mutation shifts Unc13A MUN domain closer to release sites. Drosophila NMJ electrophysiology, STED super-resolution microscopy, mathematical modeling, mutagenesis Cell reports Medium 37243591

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 605 10440375
2022 TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature 427 35197626
2022 TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature 388 35197628
1998 Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron 358 9697857
2009 Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature genetics 331 19734901
2001 Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 325 11343654
2002 Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1. The Journal of cell biology 239 12163476
1997 Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. The Journal of biological chemistry 237 8999968
2017 Synaptic weight set by Munc13-1 supramolecular assemblies. Nature neuroscience 193 29230050
2007 Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. The Journal of neuroscience : the official journal of the Society for Neuroscience 161 17267576
2013 Dynamic control of synaptic vesicle replenishment and short-term plasticity by Ca(2+)-calmodulin-Munc13-1 signaling. Neuron 138 23770256
2005 Identification of the minimal protein domain required for priming activity of Munc13-1. Current biology : CB 110 16271475
2011 UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiology of aging 109 22118904
2006 Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS biology 102 16732694
2019 Membrane bridging by Munc13-1 is crucial for neurotransmitter release. eLife 96 30816091
2003 Regulation of insulin exocytosis by Munc13-1. The Journal of biological chemistry 95 12871971
2017 Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. The Journal of clinical investigation 94 28192369
2014 C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis. Annals of neurology 94 24931836
2006 Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance. Diabetes 90 16644700
2006 Munc13-1 is required for the sustained release of insulin from pancreatic beta cells. Cell metabolism 87 16697276
2006 Binding to Rab3A-interacting molecule RIM regulates the presynaptic recruitment of Munc13-1 and ubMunc13-2. The Journal of biological chemistry 84 16704978
2009 A protein interaction node at the neurotransmitter release site: domains of Aczonin/Piccolo, Bassoon, CAST, and rim converge on the N-terminal domain of Munc13-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 19812333
2012 UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study. Neurobiology of aging 68 22921269
2019 Munc13-1 MUN domain and Munc18-1 cooperatively chaperone SNARE assembly through a tetrameric complex. Proceedings of the National Academy of Sciences of the United States of America 63 31888993
2006 Molecular dynamics of a presynaptic active zone protein studied in Munc13-1-enhanced yellow fluorescent protein knock-in mutant mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 17167095
2024 Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease. Acta neuropathologica 56 38175301
2007 Potentiation of exocytosis by phospholipase C-coupled G-protein-coupled receptors requires the priming protein Munc13-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 17202488
2016 Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurology. Genetics 55 27648472
2007 Interaction between Munc13-1 and RIM is critical for glucagon-like peptide-1 mediated rescue of exocytotic defects in Munc13-1 deficient pancreatic beta-cells. Diabetes 55 17639022
2005 Intramolecular occlusion of the diacylglycerol-binding site in the C1 domain of munc13-1. Biochemistry 51 15667202
2023 TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A. PLoS biology 45 36930682
2019 RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses. eLife 44 31535974
2023 UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target. Journal of neurology, neurosurgery, and psychiatry 43 36737245
2021 Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission. Neuron 40 34706220
2013 β-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A-RIM1α interaction to potentiate glutamate release at cerebrocortical nerve terminals. The Journal of biological chemistry 40 24036110
2021 Control of neurotransmitter release by two distinct membrane-binding faces of the Munc13-1 C1C2B region. eLife 36 34779770
2018 UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. Neurobiology of aging 36 30368160
2011 Munc13-1 is required for presynaptic long-term potentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 21849565
2015 UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort. Journal of neurology 33 26162714
2020 The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis. Annals of neurology 31 32627229
2004 Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. The Journal of biological chemistry 31 15123597
2013 The pre-synaptic Munc13-1 binds alcohol and modulates alcohol self-administration in Drosophila. Journal of neurochemistry 29 23692447
2011 Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. Traffic (Copenhagen, Denmark) 29 21689256
2019 UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 28 31201598
2024 Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs. bioRxiv : the preprint server for biology 23 38979232
2016 Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration 23 27584932
2022 Neuronal SNARE complex assembly guided by Munc18-1 and Munc13-1. FEBS open bio 22 35278279
2020 Re-examining how Munc13-1 facilitates opening of syntaxin-1. Protein science : a publication of the Protein Society 22 32086964
2021 Vesicle capture by membrane-bound Munc13-1 requires self-assembly into discrete clusters. FEBS letters 20 34227103
2001 The synaptic vesicle priming protein Munc13-1 is absent from tonically active ribbon synapses of the rat retina. Brain research 20 11259787
2022 Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial. Trials 18 36471413
2018 Spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats. Cell death & disease 18 30042425
2013 Munc13-1 Translocates to the Plasma Membrane in a Doc2B- and Calcium-Dependent Manner. Frontiers in endocrinology 18 24062723
2013 Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. The Journal of biological chemistry 15 23801330
2007 Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding. Molecular neurodegeneration 15 18067682
2023 Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation. Cell reports 14 37243591
2023 Association of the risk factor UNC13A with survival and upper motor neuron involvement in amyotrophic lateral sclerosis. Frontiers in aging neuroscience 13 36819716
2024 Differential SNARE chaperoning by Munc13-1 and Munc18-1 dictates fusion pore fate at the release site. Nature communications 11 38755165
2022 Interdomain Dynamics via Paramagnetic NMR on the Highly Flexible Complex Calmodulin/Munc13-1. Journal of the American Chemical Society 11 36082939
2022 Clinical and Metabolic Signature of UNC13A rs12608932 Variant in Amyotrophic Lateral Sclerosis. Neurology. Genetics 9 36313067
2017 Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1. Biochimica et biophysica acta. General subjects 9 28713022
2024 Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype. Journal of the neurological sciences 7 39241471
2024 Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95. bioRxiv : the preprint server for biology 6 38260705
2022 Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion. eLife 6 36214779
2020 Effect of ethanol on Munc13-1 C1 in Membrane: A Molecular Dynamics Simulation Study. Alcoholism, clinical and experimental research 6 32424866
2018 Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation. Biochemistry 6 29244485
2024 Control of Munc13-1 Activity by Autoinhibitory Interactions Involving the Variable N-terminal Region. Journal of molecular biology 5 38417672
2020 The Unc13A isoform is important for phasic release and olfactory memory formation at mushroom body synapses. Journal of neurogenetics 5 31980003
2022 Homozygous UNC13A Variant in an Infant With Congenital Encephalopathy and Severe Neuromuscular Phenotype: A Case Report With Detailed Central Nervous System Neuropathologic Findings. Cureus 4 36447687
2021 Probing the Diacylglycerol Binding Site of Presynaptic Munc13-1. Biochemistry 4 33818064
2025 Endogenous SNAP-Tagging of Munc13‑1 for Monitoring Synapse Nanoarchitecture. JACS Au 3 40575326
2025 Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nature genetics 3 41125872
2023 Correction: TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A. PLoS biology 3 37451236
2022 Differential Expression of Presynaptic Munc13-1 and Munc13-2 in Mouse Hippocampus Following Ethanol Drinking. Neuroscience 3 35167938
2019 MUNC13-1 heterozygosity does not alter voluntary ethanol consumption or sensitivity in mice. Alcohol (Fayetteville, N.Y.) 3 31265903
2026 Munc13-1 couples DAG and Ca2+ signaling to dynamic vesicle priming, synaptic short-term plasticity, and posttetanic potentiation. Science advances 2 41686904
2021 Molecular dynamics simulation studies on binding of activator and inhibitor to Munc13-1 C1 in the presence of membrane. Journal of biomolecular structure & dynamics 2 34779746
2013 Reduced expression of Munc13-1 in human and porcine diabetic peripheral nerve. Acta histochemica 2 23830992
2008 Characterization of Munc13-1 and insulin secretion during pancreatic development in rats. Journal of endocrinological investigation 2 18787382
2025 ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation. The EMBO journal 1 40707625
2023 Activation of Munc13-1 by Diacylglycerol (DAG)-Lactones. Biochemistry 1 37651159
2017 Inhibitory role of Munc13-1 in antigen-induced mast cell degranulation. Biomedical research (Tokyo, Japan) 1 29225210
2007 Expression, purification and characterization of critical domains of Munc13-1. Acta biochimica et biophysica Sinica 1 17687497
2026 Homozygosity for the C allele at UNC13A rs12608932 seems to compromise cognition in ALS independently of the cognitive domains. Amyotrophic lateral sclerosis & frontotemporal degeneration 0 41481541
2026 Ca2+-phospholipid-dependent regulation of Munc13-1 is essential for post-tetanic potentiation at mossy fiber synapses and supports working memory. Cell reports 0 41719128
2026 Guiding AlphaFold to predict how Munc13-1 opens Syntaxin-1. FEBS open bio 0 42208546
2025 Characterization of human healthy i3 lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype. Journal of the neurological sciences 0 40250093
2025 A specific negatively charged sequence confers intramolecular regulation on Munc13-1 function in synaptic exocytosis. Proceedings of the National Academy of Sciences of the United States of America 0 40489622
2025 U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis. bioRxiv : the preprint server for biology 0 41394711
2025 Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies. bioRxiv : the preprint server for biology 0 41573891
2024 Control of Munc13-1 Activity by Autoinhibitory Interactions Involving the Variable N-terminal Region. bioRxiv : the preprint server for biology 0 38328168
2023 Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment. Cells 0 37887320

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