MSH2 Protein - MutS Homolog 2

MSH2 Protein - MutS Homolog 2

Introduction

Msh2 Protein Muts Homolog 2 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<!-- Protein Infobox -->
<div class="infobox infobox-protein">
<div class="infobox-header">MSH2 Protein</div>
<div class="infobox-content">
<table>
<tr><th>Protein Name</th><td>MutS Homolog 2</td></tr>
<tr><th>Gene</th><td>[MSH2](/proteins/msh2-protein)</td></tr>
<tr><th>UniProt ID</th><td>P43246</td></tr>
<tr><th>PDB ID</th><td>2O7B, 3J95</td></tr>
<tr><th>Molecular Weight</th><td>104.7 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Nucleus</td></tr>
<tr><th>Protein Family</th><td>MutS family (ABC ATPase)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/colorectal-cancer" style="color:#ef9a9a">Colorectal Cancer</a>, <a href="/wiki/gastric-cancer" style="color:#ef9a9a">Gastric Cancer</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">50 edges</a></td>
</tr>
</table>
</div>
</div>

Overview

MSH2 Protein - MutS Homolog 2

Introduction

Msh2 Protein Muts Homolog 2 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<!-- Protein Infobox -->
<div class="infobox infobox-protein">
<div class="infobox-header">MSH2 Protein</div>
<div class="infobox-content">
<table>
<tr><th>Protein Name</th><td>MutS Homolog 2</td></tr>
<tr><th>Gene</th><td>[MSH2](/proteins/msh2-protein)</td></tr>
<tr><th>UniProt ID</th><td>P43246</td></tr>
<tr><th>PDB ID</th><td>2O7B, 3J95</td></tr>
<tr><th>Molecular Weight</th><td>104.7 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Nucleus</td></tr>
<tr><th>Protein Family</th><td>MutS family (ABC ATPase)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/colorectal-cancer" style="color:#ef9a9a">Colorectal Cancer</a>, <a href="/wiki/gastric-cancer" style="color:#ef9a9a">Gastric Cancer</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">50 edges</a></td>
</tr>
</table>
</div>
</div>

Overview

MSH2 (MutS Homolog 2) is a key DNA mismatch repair (MMR) protein essential for maintaining genomic integrity. As a core component of the MutSα (MSH2-MSH6) and MutSβ (MSH2-MSH3) heterodimers, MSH2 recognizes base-base mismatches and insertion/deletion loops that arise during DNA replication. In the brain, MSH2 plays a critical role in maintaining genomic stability in long-lived [neurons](/entities/neurons) that cannot rely on cell division to dilute accumulated DNA damage.

Structure

Domain Architecture

MSH2 contains several functional domains:

• DNA binding domain: Mismatch recognition
• ATPase domain: ABC ATPase fold for conformational changes
• MSH6/MSH3 interaction domain: Heterodimer formation

Complex Formation

• MutSα: MSH2-MSH6 heterodimer (recognizes base-base mismatches, 1-2 bp indels)
• MutSβ: MSH2-MSH3 heterodimer (recognizes larger indels up to 10 bp)

Normal Function

DNA Mismatch Repair

Brain Functions

• Maintains genomic integrity in post-mitotic neurons
• Prevents accumulation of somatic mutations
• Supports transcriptional fidelity
• Essential for neural stem cell function

Role in Neurodegeneration

Alzheimer's Disease

• DNA damage accumulates in AD neurons
• MSH2 expression altered in AD brain
• Impaired MMR contributes to genomic instability

Parkinson's Disease

• Dopaminergic neurons accumulate DNA damage
• MSH2 may be overwhelmed by oxidative stress
• Mitochondrial DNA repair interactions

Amyotrophic Lateral SALS

• Motor neurons vulnerable to DNA damage
• MSH2 dysfunction in ALS models
• Interaction with [TDP-43](/proteins/tdp-43) pathology

Therapeutic Strategies

• Enhance DNA repair capacity
• Reduce oxidative DNA damage burden
• Gene therapy to restore MSH2 expression
• Antioxidant supplementation

Mismatch Repair Function

MSH2 forms heterodimers with MSH6 (MutSα) or MSH2-MSH3 (MutSβ) to recognize:

• Base-base mismatches
• Small insertion/deletion loops
• Bulky DNA adducts

MSH2 in Cancer

Germline MSH2 mutations cause Lynch syndrome (hereditary nonpolyposis colorectal cancer):

• Autosomal dominant inheritance
• 80% lifetime cancer risk
• Early-onset colorectal, endometrial, ovarian cancers
• Microsatellite instability hallmark

• Epigenetic silencing (promoter methylation)
• Frameshift mutations
• Allelic loss

Neurological Implications

While primarily a cancer predisposition gene, MSH2 may affect neurodegeneration:

• DNA repair capacity influences neuronal survival
• Some studies link MSH2 variants to Alzheimer's disease risk
• MSH2 deficiency in neurons leads to increased mutation burden

Research Applications

MSH2 serves as a model for:

• Understanding mismatch repair mechanisms
• Developing cancer immunotherapy (MSI-high tumors)
• Studying DNA repair in neurodegeneration

See Also

• [MSH2 Gene](/proteins/msh2-protein)
• [MSH6 Protein](/proteins/msh6-protein)
• [MLH1 Protein](/proteins/mlh1-protein)
• [DNA Damage Response Pathway](/mechanisms/dna-damage-response)

External Links

• [UniProt: MSH2](https://www.uniprot.org/uniprot/P43246)
• [PDB: MSH2 structures](https://www.rcsb.org/structure/2O7B)
• [CIViC: MSH2 variants](https://civicdb.org/genes/113)
• [PubMed Search: MSH2 neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=MSH2+neurodegeneration)

Background

The study of Msh2 Protein Muts Homolog 2 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

^[1] Li GM. Cell Res. 2008;18(1):85-98. PMID: 18166976(https://pubmed.ncbi.nlm.nih.gov/18166976/)

^[2] Kunkel TA, et al. Nat Rev Mol Cell Biol. 2007;8(7):551-558. PMID: 17565350(https://pubmed.ncbi.nlm.nih.gov/17565350/)

^[3] Edelmann W, et al. Cancer Res. 2000;60(4):983-989. PMID: 10706125(https://pubmed.ncbi.nlm.nih.gov/10706125/)

^[4] Shen J, et al. Nat Rev Neurosci. 2021;22(11):681-694. PMID: 34663971(https://pubmed.ncbi.nlm.nih.gov/34663971/)

^[5] Suberbielle E, et al. Nat Neurosci. 2013;16(10):1506-1514. PMID: 24056795(https://pubmed.ncbi.nlm.nih.gov/24056795/)