Alternative titles; symbols
HGNC Approved Gene Symbol: SNAP25
Cytogenetic location: 20p12.2 Genomic coordinates (GRCh38) : 20:10,218,830-10,307,418 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.2 | ?Myasthenic syndrome, congenital, 18 | 616330 | Autosomal dominant | 3 |
Intracellular vesicles travel among cellular compartments and deliver their specific cargo to target membranes by membrane fusion. The specificity of cargo delivery and membrane fusion is controlled, in part, by the pairing of vesicle v-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) with target membrane t-SNAREs, such as SNAP25 (summary by McNew et al., 2000).
Snap25 was first investigated as a neuron-specific gene preferentially expressed in mouse hippocampus. Zhao et al. (1994) noted that it is a presynaptic plasma membrane protein that plays an important role in the synaptic vesicle membrane docking and fusion pathway. During screening of human brain-specific cDNAs by modified differential hybridization analysis, Zhao et al. (1994) found a clone that was highly and specifically expressed in adult brain and from its sequence was clearly the human homolog of mouse Snap25. The proteins predicted from the sequences of the human and mouse genes show perfect amino acid sequence conservation. SNAP25 is a 25-kD protein of 206 amino acids.
Bark and Wilson (1994) cloned 2 isoforms of SNAP25, SNAP25a and SNAP25b, from human temporal cortex and fetal brain cDNA libraries. The variants are generated by alternative splicing of 2 distinct but homologous exons, 5a and 5b, each of which encodes 39 amino acids. The 2 isoforms differ at 9 amino acids in a domain that is a substrate for posttranslational palmitoylation. Human SNAP25a and SNAP25b share 100% amino acid identity with their respective homologs in chicken and mouse. Bark and Wilson (1994) stated that Snap25a and Snap25b exhibit developmentally and anatomically distinct patterns of expression in mouse brain.
Grabs et al. (1996) demonstrated SNAP25 in conventional synaptic terminals in the retina that are absent from ribbon synapses, which play a key role in transferring information from photoreceptor cells to the central nervous system.
Gonelle-Gispert et al. (1999) found that both Snap25a and Snap25b were expressed in rodent insulin-secreting cell lines. Both proteins were expressed at the plasma membrane and in a perinuclear region.
Gonelle-Gispert et al. (1999) stated that mouse Snap25a and Snap25b induced Ca(2+)-dependent insulin secretion from a hamster insulinoma cell line. Treatment of cells with botulinum neurotoxin E resulted in cleavage of Snap25 and inhibition of Ca(2+)-induced insulin secretion.
Lipid bilayer fusion is mediated by SNAREs located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). See also 603215. The assembled v-SNARE/t-SNARE complex consists of a bundle of 4 helices, of which 1 is supplied by the v-SNARE and the other 3 by the t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin (see syntaxin 1A, 186590) supplies 1 helix and a SNAP25 protein contributes the other 2. Although there are numerous homologs with syntaxin on intracellular membranes, there are only 2 SNAP25-related proteins in yeast, Sec9 and Spo20, both of which are localized to the plasma membrane and function in secretion and sporulation, respectively. Fukuda et al. (2000) showed that an intracellular t-SNARE is built from a heavy chain homologous to syntaxin and 2 separate nonsyntaxin light chains, and concluded that SNAP25 may thus be the exception rather than the rule, having been derived from genes that encoded separate light chains that fused during evolution to produce a single gene encoding 1 protein with 2 helices.
McNew et al. (2000) tested all of the potential v-SNAREs encoded in the yeast genome for their capacity to trigger fusion by partnering with t-SNAREs that mark the Golgi, the vacuole, and the plasma membrane. McNew et al. (2000) found that, to a marked degree, the pattern of membrane flow in the cell is encoded and recapitulated by its isolated SNARE proteins, as predicted by the SNARE hypothesis. The heterodimer of syntaxin Sso1, which is homologous to syntaxin 1A, and Sec9, which is homologous to SNAP25, is a t-SNARE of the yeast plasma membrane, with Snc2, which is homologous to VAMP2 (185881), as its cognate v-SNARE. Thus, the yeast plasma membrane t-SNARE complex closely resembles its neuronal counterpart (Weber et al., 1998).
Neuronal exocytosis is triggered by calcium and requires 3 SNARE proteins: synaptobrevin (see 185880) on the synaptic vesicle, and syntaxin and SNAP25 on the plasma membrane. Neuronal SNARE proteins form a parallel 4-helix bundle that is thought to drive the fusion of opposing membranes. Hu et al. (2002) demonstrated that whereas syntaxin and SNAP25 in target membranes are freely available for SNARE complex formation, availability of synaptobrevin on synaptic vesicles is very limited. Calcium at micromolar concentrations triggers SNARE complex formation and fusion between synaptic vesicles and reconstituted target membranes. Although calcium does promote interaction of SNARE proteins between opposing membranes, it does not act by releasing synaptobrevin from synaptic vesicle restriction. Hu et al. (2002) concluded that their data suggests a mechanism in which calcium-triggered membrane apposition enables syntaxin and SNAP25 to engage synaptobrevin, leading to membrane fusion.
Ji et al. (2002) found that SNAP25 interacted with delayed rectifier K+ channels in a hamster insulinoma cell line, specifically via the Kv1.1 (KCNA1; 176260) subunit. Overexpression of SNAP25 or exogenously applied recombinant SNAP25 inhibited channel activity. Cleavage of SNAP25 by botulinum neurotoxin A light chain relieved the inhibition. Ji et al. (2002) concluded that SNAP25 mediates secretion not only through its participation in the exocytotic SNARE complex, but also by regulating membrane potential and calcium entry through its interaction with delayed rectifier K+ channels.
SNARE proteins normally face the cytoplasm, within which their helical domains can pair to link membranes for fusion. To ascertain whether SNAREs can fuse cells, Hu et al. (2003) flipped their orientation and engineered cognate cells to express either the v- or t-SNAREs. Hu et al. (2003) found that cells expressing the interacting domains of v- (VAMP2) and t-SNAREs (syntaxin-1A and SNAP25) on the cell surface fused spontaneously, demonstrating that SNAREs are sufficient to fuse biological membranes.
Tucker et al. (2004) investigated the effect of synaptotagmin I (SYT1; 185605) on membrane fusion mediated by neuronal SNARE proteins SNAP25, syntaxin (see 186590), and synaptobrevin (see 185880), which were reconstituted into vesicles. In the presence of calcium, the cytoplasmic domain of SYT1 strongly stimulated membrane fusion when synaptobrevin densities were similar to those found in native synaptic vesicles. The calcium dependence of SYT1-stimulated fusion was modulated by changes in lipid composition of the vesicles and by a truncation that mimics cleavage of SNAP25 by botulinum neurotoxin A. Stimulation of fusion was abolished by disrupting the calcium-binding activity, or by severing the tandem C2 domains, of SYT1. Thus, SYT1 and SNAREs are likely to represent the minimal protein complement for calcium-triggered exocytosis.
An and Almers (2004) monitored SNARE complex formation in vivo using a fluorescent version of SNAP25. In rat PC12 pheochromocytoma cells, they found evidence for a syntaxin-SNAP25 complex that formed with high affinity, required only the amino-terminal SNARE motif of SNAP25, tolerated a mutation that blocks formation of other syntaxin-SNAP25 complexes, and assembled reversibly when calcium entered cells during depolarization.
Nagy et al. (2004) identified mammalian Snap25a and Snap25b as targets of protein kinase A (PKA; see 176911), a key regulator of neurosecretion that primes slowly releasable pools and readily releasable pools of secretory vesicles. Mutations in Snap25a or Snap25b that mimicked Snap25 phosphorylation or dephosphorylation mirrored the effects of PKA activation and inhibition, respectively. Snap25a appeared to be the major functional isoform in chromaffin cells. The results indicated that Snap25a directly regulates the size of the slowly releasable vesicle pool.
By use of the large calyx of Held presynaptic terminal from rats, Sakaba et al. (2005) demonstrated that cleavage of different SNARE proteins by clostridial neurotoxins caused distinct kinetic changes in neurotransmitter release. When elevating calcium ion concentration directly at the presynaptic terminal with the use of caged calcium, cleavage of SNAP25 by botulinum toxin A produced a strong reduction in the calcium sensitivity for release, whereas cleavage of syntaxin using botulinum toxin C1 and synaptobrevin using tetanus toxin produced an all or nothing block without changing the kinetics of remaining vesicles. When stimulating release by calcium influx through channels, a difference between botulinum toxin C1 and tetanus toxin emerged, which suggests that cleavage of synaptobrevin modifies the coupling between channels and release-competent vesicles.
Activation of G protein-coupled receptors can inhibit Ca(2+)-dependent hormone and neurotransmitter secretion by direct inhibition of Ca(2+) influx and by a mechanism distal to Ca(2+) entry. Blackmer et al. (2005) found that Snap25 mediated the inhibitory actions of G protein beta (see GNB1; 139380)-gamma (see GNG2; 606981) dimers in rat PC12 cells. They concluded that G protein beta-gamma inhibits exocytosis by interfering with the Ca(2+)-triggered mechanism for fusion.
Gerachshenko et al. (2005) found that treatment of the lamprey central synapse with botulinum neurotoxin A or with a synthetic peptide containing the 9 C-terminal amino acids of Snap25 released by botulinum neurotoxin A prevented G protein beta-gamma-mediated inhibition of neurotransmitter release. They concluded that the C terminus of SNAP25, which links synaptotagmin I to the SNARE complex, may represent a target of G protein beta-gamma presynaptic inhibition.
Pobbati et al. (2006) found that liposome fusion was dramatically accelerated when a stabilized syntaxin/SNAP25 acceptor complex was used. Thus, SNAREs do have the capacity to execute fusion at a speed required for neuronal secretion, demonstrating that the maintenance of acceptor complexes is a critical step in biologic fusion reactions.
Mohrmann et al. (2010) used a titration approach to investigate the number of SNARE complexes needed for vesicle fusion in intact, cultured chromaffin cells. Simultaneous expression of wildtype SNAP25 and a mutant unable to support exocytosis progressively altered fusion kinetics and fusion-pore opening, indicating that both proteins assemble into heteromeric fusion complexes. Expressing different wildtype-to-mutant ratios revealed a third-power relation for fast (synchronous) fusion and a near-linear relation for overall release. Thus, Mohrmann et al. (2010) concluded that fast fusion typically observed in synapses and neurosensory cells requires at least 3 functional SNARE complexes, whereas slower release might occur with fewer complexes. Heterogeneity in SNARE complex number may explain heterogeneity in vesicular release probability.
Shi et al. (2012) used in vitro membrane fusion and exocytosis assays that paired liposomes containing a t-SNARE complex of rat syntaxin-1A and mouse Snap25 with flat nanodisc proteolipid particles containing the mouse v-SNARE Vamp2. They found that a single Vamp2 protein could mediate efficient SNARE complex formation, vesicle fusion, and lipid mixing between the liposome and nanodisc, but not pore formation or release of liposome cargo. Cargo release was highly sensitive to the number of SNARE complexes formed between the liposome and nanodisc, and maximum efflux required 3 or 4 Vamp2 proteins per nanodisc. Use of chimeric proteins revealed that the membrane-spanning transmembrane domain of VAMP2 mediated efficient release of vesicle contents by stabilizing the nascent fusion pore formed between VAMP2 and the t-SNAREs. Shi et al. (2012) concluded that membrane fusion requires only a single SNARE complex between membranes, but pore formation, widening, and stabilization, as well as efficient cargo efflux, requires several SNARE complexes.
Crystal Structure
Breidenbach and Brunger (2004) reported the first structure of a clostridial neurotoxin endopeptidase in complex with its target SNARE at a resolution of 2.1 angstroms: botulinum neurotoxin serotype A protease bound to human SNAP25. The structure, together with enzymatic kinetic data revealed an array of exosites that determine substrate specificity. Substrate orientation is similar to that of the general zinc-dependent metalloprotease thermolysin. Breidenbach and Brunger (2004) observed significant structural changes near the toxin's catalytic pocket upon substrate binding, probably serving to render the protease competent for catalysis.
Stein et al. (2009) reported the x-ray structure of the neuronal SNARE complex, consisting of the SNARE motifs of rat syntaxin-1A, Snap25, and synaptobrevin-2 (VAMP2), with the C-terminal linkers and transmembrane regions of both syntaxin-1A and synaptobrevin-2 at 3.4-angstrom resolution. The structure showed that assembly proceeds beyond the known core SNARE complex, resulting in a continuous helical bundle that is further stabilized by side-chain interactions in the linker region. The results suggested that the final phase of SNARE assembly is directly coupled to membrane merger.
Physical Chemistry
Gao et al. (2012) used optical tweezers to observe in a cell-free reconstitution experiment in real time a long-sought SNARE assembly intermediate in which only the membrane-distal amino-terminal half of the bundle is assembled. Their findings supported the zippering hypothesis, but suggested that zippering proceeds through 3 sequential binary switches, not continuously, in the amino- and carboxyl-terminal halves of the bundle and the linker domain. The half-zippered intermediate was stabilized by externally applied force that mimicked the repulsion between apposed membranes being forced to fuse. This intermediate then rapidly and forcefully zippered, delivering free energy of 36 k(B)T (where k(B) is the Boltzmann constant and T is temperature) to mediate fusion.
By study of radiation hybrids, Maglott et al. (1996) assigned the SNAP gene to a region of chromosome 20 corresponding to 20p11.2 in the cytogenetic map. The mouse Snap gene had previously been mapped to mouse chromosome 2. Maglott et al. (1996) found that the order of 3 human genes in that region is as follows: pter-SNAP-PCSK2 (162151)-THBD (188040)-cen; the order of these loci in the mouse is the same.
Congenital Myasthenic Syndrome 18
In a girl with congenital myasthenic syndrome-18 (CMS18; 616330) with intellectual disability and ataxia, Shen et al. (2014) identified a de novo heterozygous missense mutation in the SNAP25 gene (I67N; 600322.0001). The mutation, which affected the SNAP25b isoform, was found by whole-exome sequencing and confirmed by Sanger sequencing.
Associations Pending Confirmation
Feng et al. (2005) screened SNAP25 polymorphisms in 186 Canadian families with 234 ADHD children, some of whom were previously reported by Barr et al. (2000), and in an independent sample of 99 families with 102 ADHD children from southern California. Significant results were observed for 4 markers in the Canadian sample but not in the independent sample. Quantitative analysis of hyperactivity/impulsivity and inattention dimensions in the Canadian sample found that both behavioral traits were associated with SNAP25. Feng et al. (2005) noted that the different results may have been due to differences in selection criteria, ethnicity, medication response, and other clinical characteristics of the samples.
Sorensen et al. (2003) found that vesicle docking persisted, but primed vesicle pools were empty and fast calcium-triggered release was abolished, in fetal chromaffin cells from Snap25-null mice. Single vesicular fusion events were normal except for a shorter duration of the fusion pore. Overexpression of Snap25b induced larger primed vesicle pools than Snap25a. Sorensen et al. (2003) concluded that the SNAP25 isoforms differ in their ability to stabilize vesicles in the primed state.
In a mutagenesis screen, Jeans et al. (2007) identified the 'blind-drunk' (Bdr) mouse mutant, which was characterized by a subtle ataxia with otherwise grossly normal appearance, development, and brain morphology. Behavioral testing showed that blind-drunk mice had impaired sensorimotor gating, a component of the schizophrenia phenotype (181500) related to altered sensory processing. Genetic analysis of blind-drunk mice identified a dominant ile67-to-thr (I67T) missense mutation in the b isoform of Snap25. The mutation did not change the Snap25b expression level or pattern in brains of adult mutant mice, but it increased stability of the SNARE complex by forming 2 additional hydrogen bonds between Snap25b and its binding partners within the complex. Electrophysiologic analysis revealed that blind-drunk mice had an impairment in spontaneous, constitutive release of glutamate. Further analysis with mouse pancreatic beta cells demonstrated that the I67T mutation impaired exocytotic vesicle recycling and granule exocytosis and reduced the amplitude of evoked cortical excitatory postsynaptic potentials.
Oliver and Davies (2009) examined the influence of variable prenatal stress (PNS) on 2 mouse lines with mutations in the Snap25 gene: the Bdr point mutant and heterozygous Snap25-knockout mice. Neonatal development was analyzed in addition to an assessment of adult behavioral phenotypes relevant to the psychotic, cognitive, and negative aspects of schizophrenia. PNS influenced specific anxiety-related behavior in all animals. Sensorimotor gating deficits previously noted in Bdr mutants were markedly enhanced by PNS, which could be reversed by antipsychotic drugs. Social interaction abnormalities were observed only in Bdr animals from stressed dams but not in wildtype littermates or mutants from nonstressed mothers. Oliver and Davies (2009) concluded that, by combining a synaptic mouse point mutant with a controlled prenatal stressor paradigm, both modified and previously unseen phenotypes may be produced, generating new insights into the interactions between genetics and the environment relevant to the study of psychiatric disease.
In a girl with congenital myasthenic syndrome-18 (CMS18; 616330) with intellectual disability and ataxia, Shen et al. (2014) identified a de novo heterozygous c.200T-A transversion (c.200T-A, NM_130811.2) in exon 5 of the SNAP25 gene, resulting in an ile67-to-asn (I67N) substitution at a highly conserved residue that points to the center of the coiled-coil structure of the assembled SNARE complex. The mutation, which affected the SNAP25b isoform, was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not present in the Exome Variant Server, 1000 Genomes Project, or dbSNP databases. In vitro liposome fusion experiments showed that the I67N mutant interfered with calcium-induced fusion, and transfection of the mutation into chromaffin cells showed that it inhibited exocytosis of catecholamine-containing vesicles. The mutation exerted a dominant-negative effect, and Shen et al. (2014) concluded that it inhibits synaptic vesicle exocytosis.
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