Protein:TBX5 |
Protein Summary |
 Gene summary |
| Gene name: TBX5 | ASpdb.0 ID: 6910 | Gene | Gene symbol | TBX5 | Gene ID | 6910 |
| Gene name | T-box transcription factor 5 |
| Synonyms | HOS |
| Cytomap | 12q24.21 |
| Type of gene | protein-coding |
| Description | T-box transcription factor TBX5T-box 5T-box protein 5 |
| Modification date | 20240331 |
| UniProtAcc | Q99593 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | TBX5 | GO:0000978 | RNA polymerase II cis-regulatory region sequence-specific DNA binding | 26926761 |
| Gene | TBX5 | GO:0000981 | DNA-binding transcription factor activity, RNA polymerase II-specific | 29174768 |
| Gene | TBX5 | GO:0003677 | DNA binding | 16332960 |
| Gene | TBX5 | GO:0003700 | DNA-binding transcription factor activity | 11431700|12499378|16332960 |
| Gene | TBX5 | GO:0005634 | nucleus | 12237100|12499378|14519429|29174768 |
| Gene | TBX5 | GO:0005737 | cytoplasm | 14519429|29174768 |
| Gene | TBX5 | GO:0007267 | cell-cell signaling | 11161571 |
| Gene | TBX5 | GO:0007507 | heart development | 15138308 |
| Gene | TBX5 | GO:0008285 | negative regulation of cell population proliferation | 11161571|12237100 |
| Gene | TBX5 | GO:0030336 | negative regulation of cell migration | 15138308 |
| Gene | TBX5 | GO:0032991 | protein-containing complex | 26926761 |
| Gene | TBX5 | GO:0032993 | protein-DNA complex | 26926761 |
| Gene | TBX5 | GO:0043565 | sequence-specific DNA binding | 11431700|12499378 |
| Gene | TBX5 | GO:0045893 | positive regulation of DNA-templated transcription | 11431700|12499378|12845333|16332960|27035640 |
| Gene | TBX5 | GO:0045944 | positive regulation of transcription by RNA polymerase II | 29174768 |
| Gene | TBX5 | GO:0051891 | positive regulation of cardioblast differentiation | 11431700 |
| Gene | TBX5 | GO:0060039 | pericardium development | 15138308 |
| Gene | TBX5 | GO:0060044 | negative regulation of cardiac muscle cell proliferation | 11161571 |
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 |
| Q99593-1 | Q99593-1_5bqd_A.pdb | 5BQD | X-ray | 2.58 | A | 36 | 232 |
| 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 |
| Q99593 | TBX5 | Q99593-1 | Q99593-2 | 518 | 349 | 328 | 349 | Substitution | EEECSTTDHPYKKPYMETSPSE | GECDHPWSICFLSYLFLSLGWG | 328 | 349 |
| Q99593 | TBX5 | Q99593-1 | Q99593-2 | 518 | 349 | 350 | 518 | Deletion | none | none | 349 | 349 |
| Q99593 | TBX5 | Q99593-1 | Q99593-3 | 518 | 468 | 1 | 50 | Deletion | none | none | 0 | 0 |
| Multiple sequence alignment of our canonical and alternatively spliced TBX5 |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of TBX5 |
| UniProt-id | ENSG | ENST | ENSP |
| Q99593-1 | ENSG00000089225.20 | ENST00000310346.8 | ENSP00000309913.4 |
| Q99593-1 | ENSG00000089225.20 | ENST00000405440.7 | ENSP00000384152.3 |
| Q99593-2 | ENSG00000089225.20 | ENST00000526441.1 | ENSP00000433292.1 |
| Q99593-3 | ENSG00000089225.20 | ENST00000349716.9 | ENSP00000337723.5 |
| UniProt-id | NM ID | NP ID |
| Q99593-1 | NM_000192.3 | NP_000183.2 |
| Q99593-1 | NM_181486.2 | NP_852259.1 |
| Q99593-3 | NM_080717.2 | NP_542448.1 |
| Amino acid sequences of our canonical and alternatively spliced TBX5 |
| accession_id | Protein sequence |
| Q99593-1 | MADADEGFGLAHTPLEPDAKDLPCDSKPESALGAPSKSPSSPQAAFTQQGMEGIKVFLHERELWLKFHEVGTEMIITKAGRRMFPSYKVK VTGLNPKTKYILLMDIVPADDHRYKFADNKWSVTGKAEPAMPGRLYVHPDSPATGAHWMRQLVSFQKLKLTNNHLDPFGHIILNSMHKYQ PRLHIVKADENNGFGSKNTAFCTHVFPETAFIAVTSYQNHKITQLKIENNPFAKGFRGSDDMELHRMSRMQSKEYPVVPRSTVRQKVASN HSPFSSESRALSTSSNLGSQYQCENGVSGPSQDLLPPPNPYPLPQEHSQIYHCTKRKEEECSTTDHPYKKPYMETSPSEEDSFYRSSYPQ QQGLGASYRTESAQRQACMYASSAPPSEPVPSLEDISCNTWPSMPSYSSCTVTTVQPMDRLPYQHFSAHFTSGPLVPRLAGMANHGSPQL |
| Q99593-2 | MADADEGFGLAHTPLEPDAKDLPCDSKPESALGAPSKSPSSPQAAFTQQGMEGIKVFLHERELWLKFHEVGTEMIITKAGRRMFPSYKVK VTGLNPKTKYILLMDIVPADDHRYKFADNKWSVTGKAEPAMPGRLYVHPDSPATGAHWMRQLVSFQKLKLTNNHLDPFGHIILNSMHKYQ PRLHIVKADENNGFGSKNTAFCTHVFPETAFIAVTSYQNHKITQLKIENNPFAKGFRGSDDMELHRMSRMQSKEYPVVPRSTVRQKVASN |
| Q99593-3 | MEGIKVFLHERELWLKFHEVGTEMIITKAGRRMFPSYKVKVTGLNPKTKYILLMDIVPADDHRYKFADNKWSVTGKAEPAMPGRLYVHPD SPATGAHWMRQLVSFQKLKLTNNHLDPFGHIILNSMHKYQPRLHIVKADENNGFGSKNTAFCTHVFPETAFIAVTSYQNHKITQLKIENN PFAKGFRGSDDMELHRMSRMQSKEYPVVPRSTVRQKVASNHSPFSSESRALSTSSNLGSQYQCENGVSGPSQDLLPPPNPYPLPQEHSQI YHCTKRKEEECSTTDHPYKKPYMETSPSEEDSFYRSSYPQQQGLGASYRTESAQRQACMYASSAPPSEPVPSLEDISCNTWPSMPSYSSC TVTTVQPMDRLPYQHFSAHFTSGPLVPRLAGMANHGSPQLGEGMFQHQTSVAHQPVVRQCGPQTGLQSPGTLQPPEFLYSHGVPRTLSPH |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| TBX5 (go to UniProt):Q99593 |
| 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 |
| Q99593 | Region | 1 | 46 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=1;End=50 |
| Q99593 | Region | 250 | 356 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Substitution;Start=328;End=349 |
| Q99593 | Region | 250 | 356 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=350;End=518 |
| Q99593 | Compositional bias | 320 | 346 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Substitution;Start=328;End=349 |
Gene Isoform Structures and Expression Levels for TBX5 |
| Gene structures of our canonical and alternative spliced genes of TBX5 * 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 Q99593-1 |
| 3D view using mol* of Q99593-2 |
| 3D view using mol* of Q99593-3 |
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 Q99593-1 |
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| pLDDT distribution across the protein length of Q99593-2 |
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| pLDDT distribution across the protein length of Q99593-3 |
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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 Q99593-1 |
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| Ramachandran plot of Q99593-2 |
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| Ramachandran plot of Q99593-3 |
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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 |
| Q99593-1 | 1.046 | 192 | 1.088 | 547.771 | 0.551 | 0.716 | 0.948 | 0.829 | 0.863 | 0.961 | 1.269 | 48,101,103,105,106,107,108,130,131,132,133,134,135 ,137,171,172,173,174,179,182,184,186,194,195,196,1 97,199,200,201,497,498,499,500,501,502,503,504,505 |
| Q99593-2 | 1.003 | 139 | 1.048 | 429.779 | 0.679 | 0.654 | 0.845 | 0.533 | 0.871 | 0.612 | 0.799 | 44,45,46,105,106,107,108,129,130,131,132,133,134,1 64,171,172,173,174,179,182,184,201,203,205,323,325 ,326,327,328,329,330,332,333,334,335,336,337,338,3 40,341,344 |
| Q99593-3 | 0.912 | 77 | 0.868 | 270.284 | 0.579 | 0.701 | 0.984 | 0.326 | 1.158 | 0.282 | 0.527 | 10,25,31,32,33,34,35,36,38,106,166,167,173,176,177 ,180,181,182,183,186 |
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 Q99593-1_Q99593-1_5bqd_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 Q99593-1_5bqd_A_Q99593-2.pdb |
| 3D view using mol* of Q99593-1_5bqd_A_Q99593-3.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of Q99593-1_Q99593-2.pdb |
| 3D view using mol* of Q99593-1_Q99593-3.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/Q99593-1_vs_Q99593-2.png |
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| ./stats/secondary_structure/figure/Q99593-1_vs_Q99593-3.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/Q99593-1_vs_Q99593-2.png |
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| ./stats/relative_asa/Q99593-1_vs_Q99593-3.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 TBX5 |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
Related Diseases to TBX5 |
| Previous studies relating to the alternative splicing of TBX5 and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| TBX5 | 25623069 | Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. | TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons. | D000015 | Abnormalities, Multiple |
| TBX5 | 25623069 | Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. | TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons. | D006330 | Heart Defects, Congenital |
| TBX5 | 25623069 | Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. | TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons. | D006344 | Heart Septal Defects, Atrial |
| TBX5 | 25623069 | Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. | TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons. | D038061 | Lower Extremity Deformities, Congenital |
| TBX5 | 25623069 | Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. | TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons. | D038062 | Upper Extremity Deformities, Congenital |
Clinically important variants in TBX5 |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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