SNAP91 Gene

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SNAP91 — Synaptosomal-Associated Protein 91

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SNAP91 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SNAP91</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>AP180, SNAPAP, CLINT</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>6p21.1</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000165655</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10527</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5W7</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>923 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~106 kDa</td>
</tr>
<tr>
<td class="label">Tissue/Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain (hippocampus)</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Cerebellum (Purkinje cells)</td>
<td>High</td>
</tr>
<tr>
<td class="label">Striatum</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Brainstem</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spinal Cord</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Non-neuronal tissues</td>
<td>Very Low/Absent</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edg

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SNAP91 — Synaptosomal-Associated Protein 91

Overview

Mermaid diagram (expand to render)

SNAP91 (Synaptosomal-Associated Protein 91, also known as AP180) is a neuronal clathrin adaptor protein essential for synaptic vesicle endocytosis. It is encoded by the SNAP91 gene on chromosome 6p21.1 and plays a critical role in clathrin coat assembly at the presynaptic membrane. The protein functions as a peripheral membrane protein that binds to clathrin, adaptor protein complex AP-2, and phosphoinositides to promote clathrin coat assembly during synaptic vesicle recycling. SNAP91 is expressed almost exclusively in neuronal tissues, with highest expression in the [hippocampus](/brain-regions/hippocampus), cortex, and cerebellar Purkinje cells. This page covers the gene's molecular function, protein structure, disease associations, expression patterns, and key research findings relevant to neurodegeneration and neurodevelopmental disorders. [@geneprotein][@uniprot]

Gene Information

Protein Structure and Domains

The SNAP91 protein contains several distinct structural domains that mediate its function in synaptic vesicle endocytosis:

ANTH Domain (AP180 N-terminal Homology)

The N-terminal ANTH domain (approximately 300 amino acids) binds to phosphatidylinositol-4,5-bisphosphate (PIP2) on the presynaptic membrane. This domain is crucial for targeting SNAP91 to clathrin-coated pits and is structurally similar to the ENTH domain of epsin. The ANTH domain adopts a fold that creates a positively charged surface for lipid binding, facilitating membrane association during the early stages of vesicle formation.

Clathrin Box Motifs

SNAP91 contains multiple clathrin box motifs (LΦPΦXX, where Φ is a hydrophobic residue) that mediate binding to the clathrin terminal domain. These motifs allow SNAP91 to nucleate clathrin lattice assembly and stabilize the forming vesicle coat. The presence of multiple clathrin box motifs enables SNAP91 to simultaneously interact with multiple clathrin triskelia, promoting uniform coat assembly.

Flexible Linker Regions

The central region of SNAP91 contains flexible linker sequences that connect the membrane-binding domain to the clathrin-interacting regions. These linkers allow the protein to span distances between the membrane and the clathrin coat, accommodating the geometry of forming vesicles.

C-terminal Clathrin-Binding Region

The C-terminal region contains additional clathrin-binding motifs and is involved in dimerization, which may facilitate cooperative assembly of the clathrin coat.

Molecular Mechanism of Action

Synaptic Vesicle Recycling

Synaptic vesicles release neurotransmitters through exocytosis and must be efficiently recycled for continued neurotransmission. SNAP91 is a key player in the clathrin-mediated endocytosis (CME) pathway that recycles synaptic vesicles:

Vesicle Budding Initiation: SNAP91 localizes to sites of vesicle formation via its ANTH domain binding to PIP2-rich regions of the presynaptic membrane.

Clathrin Nucleation: The protein's clathrin box motifs bind to clathrin triskelia, initiating lattice assembly.

Coat Assembly: SNAP91 recruits additional clathrin and adaptor proteins (including AP-2) to build the complete vesicle coat.

Membrane Curvature: The protein helps deform the membrane into a clathrin-coated bud.

Vesicle Scission: Dynamin GTPase-mediated membrane fission releases the vesicle from the presynaptic membrane.

Uncoating: Hsc70 and auxilin remove the clathrin coat, allowing the vesicle to be refilled with neurotransmitters.

Interaction Network

SNAP91 interacts with several key proteins in the synaptic vesicle recycling machinery:

Clathrin: Direct binding via clathrin box motifs; SNAP91 nucleates clathrin lattice assembly
AP-2: Cooperative binding to the clathrin coat; coordinates cargo selection
Dynamin: Works downstream of SNAP91 for vesicle scission
Hsc70/Auxilin: Cooperate in clathrin uncoating
Synaptojanin: Dephosphorylates PIP2 to promote uncoating
APP (Amyloid Precursor Protein): SNAP91 influences APP processing and trafficking

Expression Pattern

SNAP91 exhibits highly restricted expression patterns:

Within neurons, SNAP91 is concentrated in presynaptic terminals where it colocalizes with synaptic vesicles and other endocytic proteins. Its expression is largely restricted to excitatory glutamatergic neurons, with lower expression in GABAergic interneurons.

Disease Associations

Alzheimer's Disease

SNAP91 has emerged as a relevant player in Alzheimer's disease pathogenesis through several mechanisms:

Synaptic Dysfunction: SNAP91 expression and localization are altered in AD brains. The protein's role in synaptic vesicle recycling makes it vulnerable to the synaptic degeneration that characterizes AD. Altered SNAP91 function may contribute to impaired neurotransmitter release and synaptic failure.

APP Processing: SNAP91 interacts with [amyloid precursor protein](/proteins/app-protein) (APP) and influences its trafficking and proteolytic processing. Changes in SNAP91 levels may affect the amyloidogenic pathway that generates amyloid-beta peptides. The protein localizes to endocytic compartments where APP processing occurs, positioning it to influence amyloid production.

Amyloid-Beta Effects: Studies show that amyloid-beta oligomers can disrupt synaptic vesicle recycling machinery, potentially including SNAP91-mediated pathways. This creates a feed-forward loop where amyloid accumulation impairs synaptic function.

Autism Spectrum Disorder

SNAP91 has been implicated in autism spectrum disorder through genetic and functional studies:

Genetic Findings: Rare variants in SNAP91 have been identified in individuals with ASD and intellectual disability. These variants may affect protein function, trafficking, or interactions with binding partners.

Synaptic Protein Networks: SNAP91 participates in synaptic protein interaction networks that are disrupted in ASD. The protein's role in maintaining synaptic homeostasis may be sensitive to perturbations that affect neural circuit function.

Intellectual Disability

SNAP91 variants have been linked to non-syndromic intellectual disability, highlighting the importance of proper synaptic vesicle recycling for cognitive function. Loss-of-function mutations in SNAP91 are associated with impaired cognitive development. The protein's critical role in synaptic function explains its impact on learning and memory.

Epilepsy

Altered SNAP91 expression has been reported in some forms of epilepsy, possibly related to impaired synaptic vesicle function and neurotransmitter release.

Key Research Findings

Discovery and Early Characterization

Identified as a major clathrin adaptor in neuronal tissue (1990s)
Demonstrated to be essential for clathrin coat assembly in vitro
Shown to bind specifically to neuronal membranes

Structural Studies

ANTH domain structure solved by X-ray crystallography
Lipid-binding mechanism characterized
Clathrin-binding interfaces mapped

Functional Studies

RNAi knockdown in Drosophila reveals essential role in synaptic vesicle endocytosis
Knockout mice show embryonic lethality or severe neurological defects
Conditional knockouts demonstrate cell-type specific requirements

Animal Models

Drosophila melanogaster: The Drosophila homolog lap is essential for synaptic vesicle endocytosis. lap mutants show accumulation of clathrin-coated vesicles and severe synaptic transmission defects.

Mus musculus: Whole-body knockout is embryonic lethal. Brain-specific knockouts show impaired synaptic function, learning deficits, and age-dependent neurodegeneration phenotypes.

Clinical Relevance

While SNAP91 is not a direct therapeutic target, understanding its function provides insights into:

Synaptic failure in neurodegenerative diseases

Endocytic trafficking as a therapeutic pathway

Neurodevelopmental disorders affecting synaptic function

Biomarkers — SNAP91 expression may serve as a marker of synaptic health

Cross-links

[SNAP91 Protein](/proteins/snap91-protein) — Protein-focused page
[Synaptic Vesicle Recycling](/mechanisms/synaptic-vesicle-recycling) — Pathway page
[Presynaptic Terminals](/cell-types/presynaptic-terminals) — Cell structure
[Hippocampus](/brain-regions/hippocampus) — Brain region
[Clathrin-Mediated Endocytosis](/mechanisms/clathrin-mediated-endocytosis) — Mechanism

External Links

[Ensembl: ENSG00000165655](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165655)
[NCBI Gene: 10527](https://www.ncbi.nlm.nih.gov/gene/10527)
[UniProt: Q9Y5W7](https://www.uniprot.org/uniprot/Q9Y5W7)
[GeneCards: SNAP91](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SNAP91)

References

[Zhang et al., Clathrin assembly protein AP180 (1995)](https://pubmed.ncbi.nlm.nih.gov/7782334/)

[Bennett et al., AP180 function in neurons (1998)](https://pubmed.ncbi.nlm.nih.gov/9662391/)

[Hill et al., AP180 and APP processing (2003)](https://pubmed.ncbi.nlm.nih.gov/12885774/)

[Lafon et al., AP180 in synaptic vesicle trafficking (2018)](https://pubmed.ncbi.nlm.nih.gov/29486241/)

[Ubelmann et al., Endocytic proteins in neurodegeneration (2017)](https://pubmed.ncbi.nlm.nih.gov/28126750/)

[Bojed et al., SNAP91 mutations in neurodevelopmental disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32251487/)

[Morgan et al., Clathrin adaptors in Alzheimer's disease (2006)](https://pubmed.ncbi.nlm.nih.gov/16469884/)

[Kim et al., AP180 function in synaptic transmission (2009)](https://pubmed.ncbi.nlm.nih.gov/19369651/)

[Mao et al., Synaptic vesicle endocytosis in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Ford et al., Structure of AP180 ANTH domain (2001)](https://pubmed.ncbi.nlm.nih.gov/11264583/)

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SNAP91 Gene

SNAP91 — Synaptosomal-Associated Protein 91

SNAP91 — Synaptosomal-Associated Protein 91

Overview

Gene Information

Protein Structure and Domains

ANTH Domain (AP180 N-terminal Homology)

Clathrin Box Motifs

Flexible Linker Regions

C-terminal Clathrin-Binding Region

Molecular Mechanism of Action

Synaptic Vesicle Recycling

Interaction Network

Expression Pattern

Disease Associations

Alzheimer's Disease

Autism Spectrum Disorder

Intellectual Disability

Epilepsy

Key Research Findings

Discovery and Early Characterization

Structural Studies

Functional Studies

Animal Models

Clinical Relevance

Cross-links

See Also

External Links

References