SNAP25

Synaptosomal-associated protein 25 (SNAP-25) is a t-SNARE protein that is encoded by the SNAP25 gene in humans. SNAP-25 is a component of the trans-SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.

Structure and function

Molecular machinery driving exocytosis in neuromediator release. The core SNARE complex is formed by four α-helices contributed by synaptobrevin, syntaxin and SNAP-25, synaptotagmin serves as a Ca²⁺ sensor and regulates intimately the SNARE zipping.

SNAP-25, a Q-SNARE protein, is anchored to the cytosolic face of membranes via palmitoyl side chains covalently bound to cysteine amino acid residues in the middle of the molecule. This means that SNAP-25 does not contain a trans-membrane domain.

SNAP-25 has been identified in contributing two α-helices to the SNARE complex, a four-α-helix domain complex. The SNARE complex participates in vesicle fusion, which involves the docking and merging of a vesicle with the cell membrane to bring about an exocytotic event. Synaptobrevin, a protein that is a part of the vesicle-associated membrane protein (VAMP) family, and syntaxin-1 also help form the SNARE complex by each contributing one α-helix. SNAP-25 assembles with synaptobrevin and syntaxin-1 and the selective binding of these proteins enables vesicle docking and fusion to occur at the correct location.

To form the SNARE complex, synaptobrevin, syntaxin-1, and SNAP-25 associate and begin to wrap around each other to form a coiled coil quaternary structure. The α-helices of both synaptobrevin and syntaxin-1 bind to those of SNAP-25. Synaptobrevin binds the α-helix near SNAP-25's C-terminal side, while syntaxin-1 binds the α-helix near the N-terminus.

SNAP-25 inhibits presynaptic P-, Q-, and L-type voltage-gated calcium channels and interacts with the synaptotagmin C2B domain in Ca²⁺-independent fashion. In glutamatergic synapses, SNAP-25 decreases the Ca²⁺ responsiveness, while it is naturally absent in GABAergic synapses.

Two isoforms (mRNA splice variants) of SNAP-25 exist, which are labeled A and B. There are nine amino acid residue differences between the two isoforms, including a re-localization of one of the four cysteine residues. The major characteristics of these two forms are outlined in the table below.

	SNAP25A	SNAP25B
Structure	N-terminal α-helix Random coil linker region with four cysteines clustered towards the center C-terminal α-helix	N-terminal α-helix Random coil linker region with four cysteines clustered towards the C-terminus C-terminal α-helix
Expression	Major SNAP-25 isoform in embryos and developing neural tissue Minimal expression in adult tissue except in pituitary and adrenal gland tissues	Minimal expression during development, major isoform in adult neural tissue
Localization	Diffuse	Localized to terminals and varicosities

Clinical significance

Consistent with the regulation of synaptic Ca²⁺ responsiveness, heterozygous deletion of the SNAP-25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug Adderall. Homozygous deletions of the SNAP-25 gene are lethal. Subsequent studies have suggested that at least some of the SNAP-25 gene mutations in humans might predispose to ADHD.

A genome wide association study pointed to the rs362584 polymorphism in the gene as possibly associated with the personality trait neuroticism. Botulinum toxins A, C and E cleave SNAP-25 leading to paralysis in clinically developed botulism.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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Nicotine Activity on Dopaminergic Neurons edit

Interactions

SNAP-25 has been shown to interact with:

• CPLX1,
• ITSN1,
• KIF5B,
• SNAPAP and
• STX11,
• STX1A,
• STX2,
• STX4,
• SYT1,
• Syntaxin 3,
• TRIM9, and
• VAMP2.

External links

• SNAP25 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the public domain Pfam and InterPro IPR000928