SNAP25

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

Structure and function


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

SNAP-25 has been identified in contributing two is_associated_with::α-helices to the SNARE complex, a four-α-helix domain complex. The SNARE complex participates in is_associated_with::vesicle fusion, which involves the docking and merging of a vesicle with the is_associated_with::cell membrane to bring about an exocytotic event. is_associated_with::Synaptobrevin, a protein that is a part of the is_associated_with::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 is_associated_with::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 is_associated_with::N-terminus.

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

Two isoforms (is_associated_with::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.

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 is_associated_with::dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug is_associated_with::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 is_associated_with::rs362584 polymorphism in the gene as possibly associated with the personality trait is_associated_with::neuroticism. Botulinum toxins A, C and E cleave SNAP-25 leading to is_associated_with::paralysis in clinically developed is_associated_with::botulism.

Interactions
SNAP-25 has been shown to interact with:


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