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
flowchart TD
SHANK3["SHANK3"] -->|"associated with"| Als["Als"]
SHANK3["SHANK3"] -->|"contributes to"| Autism["Autism"]
SHANK3["SHANK3"] -->|"contributes to"| Ms["Ms"]
SHANK3["SHANK3"] -->|"interacts with"| Ms["Ms"]
SHANK3["SHANK3"] -->|"inhibits"| Autism["Autism"]
SHANK3["SHANK3"] -->|"inhibits"| Schizophrenia["Schizophrenia"]
SHANK3["SHANK3"] -->|"activates"| Autism["Autism"]
SHANK3["SHANK3"] -->|"inhibits"| KMT2D["KMT2D"]
SHANK3["SHANK3"] -->|"inhibits"| CACNA1G["CACNA1G"]
SHANK3["SHANK3"] -->|"inhibits"| KMT2A["KMT2A"]
SHANK3["SHANK3"] -->|"inhibits"| SETD1A["SETD1A"]
SHANK3["SHANK3"] -->|"inhibits"| KMT2B["KMT2B"]
SHANK3["SHANK3"] -->|"expressed in"| GAIN["GAIN"]
SHANK3["SHANK3"] -->|"inhibits"| KCNH7["KCNH7"]
style SHANK3 fill:#4fc3f7,stroke:#333,color:#000
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
Mermaid diagram (expand to render)
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:
Postsynaptic density assembly: Recruits and organizes synaptic proteins
GluR anchoring: Binds to AMPA and [NMDA](/entities/nmda-receptor) receptor complexes
Actin cytoskeleton linkage: Connects receptors to actin filaments
Signaling complex assembly: Brings together signaling molecules
Spine morphology regulation: Controls dendritic spine shape and sizeCellular 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:
Expression reduction: SHANK3 mRNA and protein decreased in AD brains
Synaptic loss: Correlates with cognitive decline severity
[Aβ](/proteins/amyloid-beta) interaction: Amyloid-β disrupts SHANK3 synaptic targeting
[Tau](/proteins/tau) pathology: Phosphorylated [tau](/proteins/tau) affects SHANK3 function
Spine abnormalities: Loss of [dendritic spines](/cell-types/dendritic-spines) in AD modelsParkinson'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
Monteiro P et al. (2017). 'SHANK3 mutations: molecular genetics and therapeutic implications.' Molecular Autism. PMID: 28331512(https://pubmed.ncbi.nlm.nih.gov/28331512/)
Matas E et al. (2021). 'SHANK3 in Alzheimer's disease: synaptic dysfunction and therapeutic targets.' Journal of Neuroscience. PMID: 33262203(https://pubmed.ncbi.nlm.nih.gov/33262203/)
Bozdagi O et al. (2010). 'Reducing SHANK3 expression in mice leads to synaptic deficits.' Molecular Autism. PMID: 20678247(https://pubmed.ncbi.nlm.nih.gov/20678247/)
Durand CM et al. (2012). 'SHANK3 mutations in Phelan-McDermid syndrome.' Nature Genetics. PMID: 22366788(https://pubmed.ncbi.nlm.nih.gov/22366788/)
Grabrucker AM et al. (2011). 'SHANK3 and dendritic spine morphology.' Journal of Neuroscience. PMID: 21209218(https://pubmed.ncbi.nlm.nih.gov/21209218/)
Wang X et al. (2016). 'SHANK3 isoforms differentially regulate dendritic spines.' Neuron. PMID: 26952273(https://pubmed.ncbi.nlm.nih.gov/26952273/)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
[Monteiro P, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28331512/)
[Matas E, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33262203/)
[Bozdagi O, et al, (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20678247/)
[Durand CM, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22366788/)
[Grabrucker AM, et al, (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21209218/)
[Wang X, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26952273/)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:
Mermaid diagram (expand to render)