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.
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<div class="infobox-header">MSH2 Protein</div>
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<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>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">50 edges</a></td>
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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
- 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
Mismatch recognition: MutSα or MutSβ binds to DNA mismatches
Complex assembly: Recruits MutLα (MLH1-PMS2)
Strand discrimination: Identifies the newly synthesized strand
Excision: Removal of the mismatched region
Resynthesis: DNA polymerase fills the gap
Ligation: Seals the nickBrain 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
Upon binding to mismatched DNA, MSH2 undergoes conformational changes that initiate the mismatch repair cascade.
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
Somatic MSH2 inactivation occurs in sporadic cancers through:
- 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
<sup>[1]</sup> Li GM. Cell Res. 2008;18(1):85-98. PMID: 18166976(https://pubmed.ncbi.nlm.nih.gov/18166976/)
<sup>[2]</sup> Kunkel TA, et al. Nat Rev Mol Cell Biol. 2007;8(7):551-558. PMID: 17565350(https://pubmed.ncbi.nlm.nih.gov/17565350/)
<sup>[3]</sup> Edelmann W, et al. Cancer Res. 2000;60(4):983-989. PMID: 10706125(https://pubmed.ncbi.nlm.nih.gov/10706125/)
<sup>[4]</sup> Shen J, et al. Nat Rev Neurosci. 2021;22(11):681-694. PMID: 34663971(https://pubmed.ncbi.nlm.nih.gov/34663971/)
<sup>[5]</sup> Suberbielle E, et al. Nat Neurosci. 2013;16(10):1506-1514. PMID: 24056795(https://pubmed.ncbi.nlm.nih.gov/24056795/)