SHANK3 - SH3 and Multiple Ankyrin Repeat Domains 3

SHANK3 - SH3 and Multiple Ankyrin Repeat Domains 3

Introduction

Shank3 Sh3 And Multiple Ankyrin Repeat Domains 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

SHANK3 (SH3 and Multiple Ankyrin Repeat Domains 3) is a critical synaptic scaffolding protein essential for synapse formation, function, and plasticity. It is encoded by the SHANK3 gene located on chromosome 22q13.33. Also known as PROSAP2, SHANK3 is one of the most enriched proteins in the postsynaptic density (PSD) and plays a central role in organizing the synaptic machinery. [@matas2021]

SHANK3 - SH3 and Multiple Ankyrin Repeat Domains 3

Introduction

Shank3 Sh3 And Multiple Ankyrin Repeat Domains 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

SHANK3 (SH3 and Multiple Ankyrin Repeat Domains 3) is a critical synaptic scaffolding protein essential for synapse formation, function, and plasticity. It is encoded by the SHANK3 gene located on chromosome 22q13.33. Also known as PROSAP2, SHANK3 is one of the most enriched proteins in the postsynaptic density (PSD) and plays a central role in organizing the synaptic machinery. [@matas2021]

<div class="infobox infobox-gene"> [@bozdagi2010]
<table> [@durand2012]
<tr><th colspan="2" style="background:#f0f0f0;">SHANK3</th></tr> [@grabrucker2011]
<tr><td><strong>Gene Symbol</strong></td><td>SHANK3</td></tr> [@wang2016]
<tr><td><strong>Full Name</strong></td><td>SH3 and Multiple Ankyrin Repeat Domains 3</td></tr>
<tr><td><strong>Chromosome</strong></td><td>22q13.33</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[85358](https://www.ncbi.nlm.nih.gov/gene/85358)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000132924](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132924)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9BYB0](https://www.uniprot.org/uniprot/Q9BYB0)</td></tr>
<tr><td><strong>Protein Length</strong></td><td>1,620 amino acids</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~180 kDa</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>
</div>

Protein Structure

SHANK3 contains multiple protein-protein interaction domains:

| Domain | Position | Function |
|--------|----------|----------|
| ANK repeats | N-terminal (6 repeats) | Bind to actin cytoskeleton |
| SH3 domain | Central | Proline-rich motif binding |
| PDZ domain | Central | S/T-X-V/L motif binding |
| Proline-rich region | C-terminal | Various protein interactions |
| SAM domain | C-terminal | Multimerization |

Normal Function

Synaptic Scaffold

SHANK3 is a master organizer of the postsynaptic density:

Cellular Localization

• Postsynaptic densities of excitatory synapses
• [Dendritic spines](/cell-types/dendritic-spines): Primarily in mushroom and stubby spines
• Axon initial segment: Also present in some neuronal subtypes
• Synaptic vesicles: Minor presence

Expression Pattern

SHANK3 exhibits brain-region specific expression:

| Brain Region | Expression Level |
|--------------|-----------------|
| Cerebral [cortex](/brain-regions/cortex) | High |
| [Hippocampus](/brain-regions/hippocampus) | High (CA1-CA3, DG) |
| Striatum | High |
| Cerebellum | Moderate |
| Thalamus | Moderate |
| Spinal cord | Lower |

Role in Neurodegeneration

Alzheimer's Disease

SHANK3 alterations in AD:

Parkinson's Disease

• SHANK3 dysregulation in PD models
• Dopaminergic neuron synaptic deficits
• [α-synuclein](/proteins/alpha-synuclein) interaction may affect SHANK3
• LRRK2 mutations alter SHANK3 distribution

Autism Spectrum Disorder (ASD)

SHANK3 is one of the most important ASD risk genes:

• 22q13.3 deletion syndrome (Phelan-McDermid): Caused by SHANK3 haploinsufficiency
• ~1% of ASD cases: Involve SHANK3 mutations
• Core symptoms: Impaired social interaction, language deficits, intellectual disability
• Synaptic dysfunction: Impaired excitatory neurotransmission

Schizophrenia

• SHANK3 copy number variations associated with risk
• Altered synaptic plasticity
• Cognitive deficits
• Dysregulated NMDA receptor signaling

Animal Models

| Model | Key Findings | Reference |
|-------|--------------|-----------|
| SHANK3 knockout mice | Reduced synaptic proteins, social deficits | PMID: 21885688(https://pubmed.ncbi.nlm.nih.gov/21885688/) |
| SHANK3 knockdown | Impaired [LTP](/mechanisms/long-term-potentiation), behavior abnormalities | PMID: 22932670(https://pubmed.ncbi.nlm.nih.gov/22932670/) |
| SHANK3 transgenic | Rescue of synaptic defects | PMID: 24662623(https://pubmed.ncbi.nlm.nih.gov/24662623/) |

Therapeutic Implications

| Strategy | Approach | Status |
|----------|----------|--------|
| Gene therapy | Viral SHANK3 delivery | Preclinical |
| Small molecules | Upregulate endogenous SHANK3 | Research |
| ASO therapy | Splice-modulating approaches | Research |
| Cell therapy | Stem cell-derived [neurons](/entities/neurons) | Future |

Key Publications

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Autism Spectrum Disorder](/diseases/autism)
• [Synaptic Dysfunction](/mechanisms/synaptic-dysfunction-pathway)
• [Postsynaptic Density](/psd-95-)
• [PSD-95](/proteins/psd95-protein)
• [Dendritic Spines](/mechanisms/dendritic-spines)
• [AMPA Receptors](/entities/ampa-receptors)
• [NMDA Receptors](/entities/nmda-receptors)

External Links

• [NCBI Gene: SHANK3](https://www.ncbi.nlm.nih.gov/gene/85358)
• [UniProt: Q9BYB0](https://www.uniprot.org/uniprot/Q9BYB0)
• [GeneCards: SHANK3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SHANK3)
• [OMIM: SHANK3](https://www.omim.org/entry/606230)
• [SFARI Gene: SHANK3](https://gene.sfari.org/database/gene-summary/SHANK3/)

Background

The study of Shank3 Sh3 And Multiple Ankyrin Repeat Domains 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

Pathway Diagram

The following diagram shows the key molecular relationships involving SHANK3 - SH3 and Multiple Ankyrin Repeat Domains 3 discovered through SciDEX knowledge graph analysis: