DLG4 Protein

DLG4 Protein (Discs Large Homolog 4 / PSD-95)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">DLG4</th></tr>
<tr><td><b>Gene</b></td><td>[DLG4](/genes/dlg4)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P78352](https://www.uniprot.org/uniprot/P78352)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>95 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Postsynaptic density, excitatory synapses</td></tr>
<tr><td><b>Protein Family</b></td><td>PSD95 family, MAGUK family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/tinnitus" style="color:#ef9a9a">Tinnitus</a>, <a href="/wiki/williams'-syndrome" style="color:#ef9a9a">Williams' syndrome</a>, <a href="/wiki/autism-spectrum-disorders" style="color:#ef9a9a">autism spectrum disorders</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">42 edges</a></td>
</tr>
</table>
</div>

Overview

DLG4 (Discs Large Homolog 4), more commonly known as PSD-95, is a core scaffold protein of the postsynaptic density that organizes excitatory synapses. The [DLG4](/genes/dlg4) gene encodes a 724-amino acid protein essential for synaptic structure, function, and plasticity.

Structure

PSD-95 contains multiple protein-interaction domains:

DLG4 Protein (Discs Large Homolog 4 / PSD-95)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">DLG4</th></tr>
<tr><td><b>Gene</b></td><td>[DLG4](/genes/dlg4)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P78352](https://www.uniprot.org/uniprot/P78352)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>95 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Postsynaptic density, excitatory synapses</td></tr>
<tr><td><b>Protein Family</b></td><td>PSD95 family, MAGUK family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/tinnitus" style="color:#ef9a9a">Tinnitus</a>, <a href="/wiki/williams'-syndrome" style="color:#ef9a9a">Williams' syndrome</a>, <a href="/wiki/autism-spectrum-disorders" style="color:#ef9a9a">autism spectrum disorders</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">42 edges</a></td>
</tr>
</table>
</div>

Overview

DLG4 (Discs Large Homolog 4), more commonly known as PSD-95, is a core scaffold protein of the postsynaptic density that organizes excitatory synapses. The [DLG4](/genes/dlg4) gene encodes a 724-amino acid protein essential for synaptic structure, function, and plasticity.

Structure

PSD-95 contains multiple protein-interaction domains:

| Domain | Position | Function |
|--------|----------|----------|
| PDZ domains (3) | N-terminal | Bind C-terminal motifs of receptors/ion channels |
| SH3 domain | Middle | Protein-protein interactions |
| GK domain | C-terminal | Bind guanylate kinase-associated proteins |

This modular architecture allows PSD-95 to assemble large signaling complexes at synapses.

Biological Function

Synaptic Scaffold

PSD-95 organizes the postsynaptic density:

Synaptic Plasticity

PSD-95 is critical for learning and memory:

• Regulates [long-term potentiation](/mechanisms/long-term-potentiation) (LTP)
• Controls long-term depression (LTD)
• Modulates spine morphology
• Activity-dependent modifications

Protein Interactions

Key PSD-95 interacting proteins:

• GluA1-4: AMPA receptor subunits
• NR1, NR2A/B: NMDA receptor subunits
• AKAP79/150: A-kinase anchoring proteins
• SynGAP: Ras GTPase-activating protein
• nNOS: Neuronal nitric oxide synthase

Role in Neurodegeneration

Alzheimer's Disease

PSD-95 alterations contribute to synaptic failure in AD:

Parkinson's Disease

• Dopaminergic synapses: PSD-95 in striatal medium spiny [neurons](/entities/neurons)
• Excitotoxicity: NMDA receptor dysregulation
• Synaptic pruning: Altered PSD-95 in disease models

Therapeutic Potential

Targeting PSD-95 interactions shows promise:

• Neuroprotective peptides: Mimetic peptides preserving synapses
• Small molecule modulators: Stabilize PSD-95 interactions
• Gene therapy: Restore PSD-95 expression

Genetic Associations

DLG4 polymorphisms have been linked to:

• Schizophrenia
• Autism spectrum disorders
• Intellectual disability
• neurodegenerative disease progression

See Also

• [DLG4 Gene](/genes/dlg4)

External Links

• [GeneCards: DLG4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLG4)

Synaptic Pathology in Disease

DLG4/PSD-95 changes in neurological disorders:

Alzheimer's Disease

• Reduced PSD-95 levels in AD hippocampus
• Loss of dendritic spines
• Impaired synaptic transmission
• Correlation with cognitive decline

Parkinson's Disease

• Altered striatal PSD-95
• Dysregulated NMDA receptor signaling
• Excitotoxicity vulnerability

Therapeutic Strategies

Targeting PSD-95:

• Peptide mimetics: Cell-permeable PSD-95 inhibitors
• Gene therapy: Viral vector delivery
• Small molecules: Stabilizing PSD-95 interactions

Animal Models

• Dlg4 knockout mice: Lethal phenotypes
• Transgenic models: Overexpression studies
• Conditional knockouts: Brain-specific deletion

Alternative Splicing

DLG4 splice variants:

• PSD-95 alpha: Full-length isoform
• PSD-95 beta: Missing N-terminal PDZ domain
• PSD-95 gamma: Alternative C-terminus
• Developmental regulation: Isoform switching

References