Protein:MSH2 |
Protein Summary |
 Gene summary |
| Gene name: MSH2 | ASpdb.0 ID: 4436 | Gene | Gene symbol | MSH2 | Gene ID | 4436 |
| Gene name | mutS homolog 2 |
| Synonyms | COCA1|FCC1|HNPCC|HNPCC1|LCFS2|LYNCH1|MMRCS2|MSH-2|hMSH2 |
| Cytomap | 2p21-p16.3 |
| Type of gene | protein-coding |
| Description | DNA mismatch repair protein Msh2DNA mismatch repair protein Msh2 transcriptMutS-like 2mutS homolog 2, colon cancer, nonpolyposis type 1 |
| Modification date | 20240407 |
| UniProtAcc | P43246 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | MSH2 | GO:0000287 | magnesium ion binding | 16403449 |
| Gene | MSH2 | GO:0000400 | four-way junction DNA binding | 12034830 |
| Gene | MSH2 | GO:0003677 | DNA binding | 7923193 |
| Gene | MSH2 | GO:0003682 | chromatin binding | 26300262 |
| Gene | MSH2 | GO:0003690 | double-stranded DNA binding | 11809883 |
| Gene | MSH2 | GO:0003697 | single-stranded DNA binding | 11809883 |
| Gene | MSH2 | GO:0005524 | ATP binding | 15105434 |
| Gene | MSH2 | GO:0005634 | nucleus | 26300262 |
| Gene | MSH2 | GO:0005654 | nucleoplasm | - |
| Gene | MSH2 | GO:0006281 | DNA repair | 8942985 |
| Gene | MSH2 | GO:0006298 | mismatch repair | 11555625 |
| Gene | MSH2 | GO:0006298 | mismatch repair | 7923193|9677427 |
| Gene | MSH2 | GO:0006301 | postreplication repair | 7923193 |
| Gene | MSH2 | GO:0008094 | ATP-dependent activity, acting on DNA | 16403449 |
| Gene | MSH2 | GO:0030983 | mismatched DNA binding | 8942985|11756455|11801590 |
| Gene | MSH2 | GO:0032137 | guanine/thymine mispair binding | 8942985|11809883 |
| Gene | MSH2 | GO:0032139 | dinucleotide insertion or deletion binding | 8942985 |
| Gene | MSH2 | GO:0032142 | single guanine insertion binding | 8942985 |
| Gene | MSH2 | GO:0032143 | single thymine insertion binding | 8942985 |
| Gene | MSH2 | GO:0032181 | dinucleotide repeat insertion binding | 8942985 |
| Gene | MSH2 | GO:0032301 | MutSalpha complex | 8942985|23622243 |
| Gene | MSH2 | GO:0032302 | MutSbeta complex | 8942985 |
| Gene | MSH2 | GO:0032357 | oxidized purine DNA binding | 11756455|11801590 |
| Gene | MSH2 | GO:0032405 | MutLalpha complex binding | 16403449 |
| Gene | MSH2 | GO:0042803 | protein homodimerization activity | 8942985 |
| Gene | MSH2 | GO:0043531 | ADP binding | 15105434 |
| Gene | MSH2 | GO:0045910 | negative regulation of DNA recombination | 17715146 |
| Gene | MSH2 | GO:0051096 | positive regulation of helicase activity | 17715146 |
AS Summary |
| Information of the canonical protein with experimentally identified structure from PDB (2023). |
| UniProt Acc | File name | PDB ID | Method | Resolution | Chain | Start | End |
| P43246-1 | P43246-1_3thw_A.pdb | 3THW | X-ray | 3.09 | A | 11 | 930 |
| ASpdb's canonical and alternatively spliced isoform information. |
| accession_id | gene_name | canonical_id | alternative_id | canonical_length | alternative_length | canonical_start | canonical_end | type | originalSEQ | variationSEQ | alternative_start | alternative_end |
| P43246 | MSH2 | P43246-1 | P43246-2 | 934 | 868 | 1 | 66 | Deletion | none | none | 0 | 0 |
| Multiple sequence alignment of our canonical and alternatively spliced MSH2 |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of MSH2 |
| UniProt-id | ENSG | ENST | ENSP |
| P43246-1 | ENSG00000095002.15 | ENST00000233146.7 | ENSP00000233146.2 |
| P43246-2 | ENSG00000095002.15 | ENST00000543555.6 | ENSP00000442697.1 |
| UniProt-id | NM ID | NP ID |
| P43246-1 | NM_000251.2 | NP_000242.1 |
| P43246-2 | NM_001258281.1 | NP_001245210.1 |
| Amino acid sequences of our canonical and alternatively spliced MSH2 |
| accession_id | Protein sequence |
| P43246-1 | MAVQPKETLQLESAAEVGFVRFFQGMPEKPTTTVRLFDRGDFYTAHGEDALLAAREVFKTQGVIKYMGPAGAKNLQSVVLSKMNFESFVK DLLLVRQYRVEVYKNRAGNKASKENDWYLAYKASPGNLSQFEDILFGNNDMSASIGVVGVKMSAVDGQRQVGVGYVDSIQRKLGLCEFPD NDQFSNLEALLIQIGPKECVLPGGETAGDMGKLRQIIQRGGILITERKKADFSTKDIYQDLNRLLKGKKGEQMNSAVLPEMENQVAVSSL SAVIKFLELLSDDSNFGQFELTTFDFSQYMKLDIAAVRALNLFQGSVEDTTGSQSLAALLNKCKTPQGQRLVNQWIKQPLMDKNRIEERL NLVEAFVEDAELRQTLQEDLLRRFPDLNRLAKKFQRQAANLQDCYRLYQGINQLPNVIQALEKHEGKHQKLLLAVFVTPLTDLRSDFSKF QEMIETTLDMDQVENHEFLVKPSFDPNLSELREIMNDLEKKMQSTLISAARDLGLDPGKQIKLDSSAQFGYYFRVTCKEEKVLRNNKNFS TVDIQKNGVKFTNSKLTSLNEEYTKNKTEYEEAQDAIVKEIVNISSGYVEPMQTLNDVLAQLDAVVSFAHVSNGAPVPYVRPAILEKGQG RIILKASRHACVEVQDEIAFIPNDVYFEKDKQMFHIITGPNMGGKSTYIRQTGVIVLMAQIGCFVPCESAEVSIVDCILARVGAGDSQLK GVSTFMAEMLETASILRSATKDSLIIIDELGRGTSTYDGFGLAWAISEYIATKIGAFCMFATHFHELTALANQIPTVNNLHVTALTTEET LTMLYQVKKGVCDQSFGIHVAELANFPKHVIECAKQKALELEEFQYIGESQGYDIMEPAAKKCYLEREQGEKIIQEFLSKVKQMPFTEMS |
| P43246-2 | MGPAGAKNLQSVVLSKMNFESFVKDLLLVRQYRVEVYKNRAGNKASKENDWYLAYKASPGNLSQFEDILFGNNDMSASIGVVGVKMSAVD GQRQVGVGYVDSIQRKLGLCEFPDNDQFSNLEALLIQIGPKECVLPGGETAGDMGKLRQIIQRGGILITERKKADFSTKDIYQDLNRLLK GKKGEQMNSAVLPEMENQVAVSSLSAVIKFLELLSDDSNFGQFELTTFDFSQYMKLDIAAVRALNLFQGSVEDTTGSQSLAALLNKCKTP QGQRLVNQWIKQPLMDKNRIEERLNLVEAFVEDAELRQTLQEDLLRRFPDLNRLAKKFQRQAANLQDCYRLYQGINQLPNVIQALEKHEG KHQKLLLAVFVTPLTDLRSDFSKFQEMIETTLDMDQVENHEFLVKPSFDPNLSELREIMNDLEKKMQSTLISAARDLGLDPGKQIKLDSS AQFGYYFRVTCKEEKVLRNNKNFSTVDIQKNGVKFTNSKLTSLNEEYTKNKTEYEEAQDAIVKEIVNISSGYVEPMQTLNDVLAQLDAVV SFAHVSNGAPVPYVRPAILEKGQGRIILKASRHACVEVQDEIAFIPNDVYFEKDKQMFHIITGPNMGGKSTYIRQTGVIVLMAQIGCFVP CESAEVSIVDCILARVGAGDSQLKGVSTFMAEMLETASILRSATKDSLIIIDELGRGTSTYDGFGLAWAISEYIATKIGAFCMFATHFHE LTALANQIPTVNNLHVTALTTEETLTMLYQVKKGVCDQSFGIHVAELANFPKHVIECAKQKALELEEFQYIGESQGYDIMEPAAKKCYLE |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| MSH2 (go to UniProt):P43246 |
| Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained protein feature among the 13 regional features. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
Gene Isoform Structures and Expression Levels for MSH2 |
| Gene structures of our canonical and alternative spliced genes of MSH2 * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Expression levels of gene isoforms across GTEx. |
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| Expression levels of gene isoforms across TCGA. |
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Protein Structures |
| PDB and CIF files of the predicted protein structures * Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format. |
| 3D view using mol* of P43246-1 |
| 3D view using mol* of P43246-2 |
pLDDT Score Distribution |
| pLDDT score distribution of the predicted protein structures from AlphaFold2 * AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. |
| pLDDT distribution across the protein length of P43246-1 |
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| pLDDT distribution across the protein length of P43246-2 |
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Ramachandran Plot of Protein Structures |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide. |
| Ramachandran plot of P43246-1 |
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| Ramachandran plot of P43246-2 |
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Potential Active Site Information |
| The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite. |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| P43246-1 | 1.101 | 126 | 1.127 | 317.961 | 0.4 | 0.818 | 1.102 | 1.589 | 0.93 | 1.709 | 0.67 | 182,183,188,212,215,216,219,303,304,305,308,710,71 4,715,716,717,720,722,723,724,727,730,731,734,735, 737 |
| P43246-2 | 1 | 455 | 1.007 | 1418.648 | 0.619 | 0.698 | 0.895 | 0.411 | 1.081 | 0.381 | 0.715 | 27,28,31,59,62,70,74,75,76,77,78,79,80,99,101,103, 104,105,106,107,108,122,125,126,127,128,129,130,13 1,152,153,154,155,156,179,180,181,182,185,186,187, 188,191,192,221,222,223,224,225,226,228,233,238,24 1,242,245,247,248,249,250,251,253,254,256,257,258, 259,261,262,265,271,273,274,275,277,278,279,281,28 2,284,289,292,293,322,325,326,329,369,520,523,524, 527,530,531,534,535 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of P43246-1_P43246-1_3thw_A.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P43246-1_3thw_A_P43246-2.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P43246-1_P43246-2.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/P43246-1_vs_P43246-2.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/P43246-1_vs_P43246-2.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to MSH2 |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
Related Diseases to MSH2 |
| Previous studies relating to the alternative splicing of MSH2 and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| MSH2 | 9490293 | Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. | The phenomenon of alternative splicing in the DNA mismatch repair genes MLH1 and MSH2 was extensively investigated by coupled reverse transcription-polymerase chain reaction in different human tissues, including 42 mononuclear blood cell samples--31 obtained from familial colon cancer patients or their at-risk relatives and 11 from healthy blood donors--7 normal colonic mucosae, 4 established human cancer cell lines, 8 colorectal tumors, and one sample each of ileum, liver, muscle, thymus, breast, and EBV-transformed lymphoblasts. Several isoforms were observed for each gene. Products of MLH1 alternative splicing included mRNAs lacking alternative exons 6/9, 9, 9/10, 9/10/11, 10/11, 12, 16, and 17. For MSH2, products lacking exons 5, 13, 2 through 7, and 2 through 8 were identified. The levels of expression were found to vary among different samples. All isoforms were found in a relevant fraction (43-100%) of the mononuclear blood cell samples, as well as in other tissues. The splicing variants were also detected in normal colonic mucosa, with the exceptions of the MLH1 -6/9 and -10/11 and the MSH2 -13 isoforms. Germline mutations of MLH1 and MSH2 confer constitutional predisposition to the development of colorectal cancer and other neoplasms. A substantial proportion of the mutations identified so far involve alterations of the normal splicing process. Knowledge of the existence of multiple alternative splicing events, not caused by genomic DNA changes, is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis. | D003123 | Colorectal Neoplasms, Hereditary Nonpolyposis |
| MSH2 | 9490293 | Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. | The phenomenon of alternative splicing in the DNA mismatch repair genes MLH1 and MSH2 was extensively investigated by coupled reverse transcription-polymerase chain reaction in different human tissues, including 42 mononuclear blood cell samples--31 obtained from familial colon cancer patients or their at-risk relatives and 11 from healthy blood donors--7 normal colonic mucosae, 4 established human cancer cell lines, 8 colorectal tumors, and one sample each of ileum, liver, muscle, thymus, breast, and EBV-transformed lymphoblasts. Several isoforms were observed for each gene. Products of MLH1 alternative splicing included mRNAs lacking alternative exons 6/9, 9, 9/10, 9/10/11, 10/11, 12, 16, and 17. For MSH2, products lacking exons 5, 13, 2 through 7, and 2 through 8 were identified. The levels of expression were found to vary among different samples. All isoforms were found in a relevant fraction (43-100%) of the mononuclear blood cell samples, as well as in other tissues. The splicing variants were also detected in normal colonic mucosa, with the exceptions of the MLH1 -6/9 and -10/11 and the MSH2 -13 isoforms. Germline mutations of MLH1 and MSH2 confer constitutional predisposition to the development of colorectal cancer and other neoplasms. A substantial proportion of the mutations identified so far involve alterations of the normal splicing process. Knowledge of the existence of multiple alternative splicing events, not caused by genomic DNA changes, is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis. | D004198 | Disease Susceptibility |
| MSH2 | 20403997 | Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. | Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide. | D015179 | Colorectal Neoplasms |
| MSH2 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| MSH2 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| MSH2 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
Clinically important variants in MSH2 |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
| P43246 | P43246-1 | MSH2 | Indel | p.Thr438_Ser445delinsPheSerLysPheGlnGluMetIle | Pathogenic |
| P43246 | P43246-1 | MSH2 | Indel | p.Thr438_Ser445delinsPheSerLysPheGlnGluMetIle | Pathogenic |
| P43246 | P43246-1 | MSH2 | Duplication | p.Ile704Metfs | Pathogenic |
| P43246 | P43246-1 | MSH2 | Duplication | p.Ile704Metfs | Pathogenic |
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