Protein:KDM1A |
Protein Summary |
 Gene summary |
| Gene name: KDM1A | ASpdb.0 ID: 23028 | Gene | Gene symbol | KDM1A | Gene ID | 23028 |
| Gene name | lysine demethylase 1A |
| Synonyms | AOF2|BHC110|CPRF|KDM1|LSD1 |
| Cytomap | 1p36.12 |
| Type of gene | protein-coding |
| Description | lysine-specific histone demethylase 1ABRAF35-HDAC complex protein BHC110FAD-binding protein BRAF35-HDAC complex, 110 kDa subunit[histone H3]-dimethyl-L-lysine(4) FAD-dependent demethylase 1Aamine oxidase (flavin containing) domain 2flavin-containing |
| Modification date | 20240411 |
| UniProtAcc | O60341 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | KDM1A | GO:0000781 | chromosome, telomeric region | 24529708 |
| Gene | KDM1A | GO:0000785 | chromatin | 17277772 |
| Gene | KDM1A | GO:0003682 | chromatin binding | 16079795|20228790|24217620|33980486 |
| Gene | KDM1A | GO:0003713 | transcription coactivator activity | 20833138 |
| Gene | KDM1A | GO:0005634 | nucleus | 33980486 |
| Gene | KDM1A | GO:0005634 | nucleus | 16079795|19497860 |
| Gene | KDM1A | GO:0005654 | nucleoplasm | - |
| Gene | KDM1A | GO:0016491 | oxidoreductase activity | 15620353 |
| Gene | KDM1A | GO:0032452 | histone demethylase activity | 19497860 |
| Gene | KDM1A | GO:0032453 | histone H3K4 demethylase activity | 15620353|24217620 |
| Gene | KDM1A | GO:0032454 | histone H3K9 demethylase activity | 16079795|20228790 |
| Gene | KDM1A | GO:0032991 | protein-containing complex | 24217620 |
| Gene | KDM1A | GO:0034644 | cellular response to UV | 24217620 |
| Gene | KDM1A | GO:0042162 | telomeric DNA binding | 24529708 |
| Gene | KDM1A | GO:0043426 | MRF binding | 20833138 |
| Gene | KDM1A | GO:0043433 | negative regulation of DNA-binding transcription factor activity | 19497860 |
| Gene | KDM1A | GO:0045892 | negative regulation of DNA-templated transcription | 19497860 |
| Gene | KDM1A | GO:0045944 | positive regulation of transcription by RNA polymerase II | 20833138 |
| Gene | KDM1A | GO:0050660 | flavin adenine dinucleotide binding | 15620353 |
| Gene | KDM1A | GO:0050681 | nuclear androgen receptor binding | 16079795 |
| Gene | KDM1A | GO:0061752 | telomeric repeat-containing RNA binding | 24529708 |
| Gene | KDM1A | GO:0090308 | regulation of DNA methylation-dependent heterochromatin formation | 33980486 |
| Gene | KDM1A | GO:0140297 | DNA-binding transcription factor binding | 20833138 |
| Gene | KDM1A | GO:0140682 | FAD-dependent H3K4me/H3K4me3 demethylase activity | 20228790 |
| Gene | KDM1A | GO:0140861 | DNA repair-dependent chromatin remodeling | 24217620 |
| Gene | KDM1A | GO:1990391 | DNA repair complex | 24217620 |
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 |
| O60341-1 | O60341-1_2iw5_A.pdb | 2IW5 | X-ray | 2.57 | A | 171 | 836 |
| 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 |
| O60341 | KDM1A | O60341-1 | O60341-2 | 852 | 876 | 173 | 173 | Substitution | G | GQAGGLQDDSSGGYGDGQASG | 173 | 193 |
| O60341 | KDM1A | O60341-1 | O60341-2 | 852 | 876 | 369 | 369 | Substitution | A | ADTVK | 389 | 393 |
| Multiple sequence alignment of our canonical and alternatively spliced KDM1A |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of KDM1A |
| UniProt-id | ENSG | ENST | ENSP |
| O60341-1 | ENSG00000004487.18 | ENST00000356634.7 | ENSP00000349049.3 |
| O60341-2 | ENSG00000004487.18 | ENST00000400181.9 | ENSP00000383042.5 |
| UniProt-id | NM ID | NP ID |
| O60341-1 | NM_015013.3 | NP_055828.2 |
| O60341-2 | NM_001009999.2 | NP_001009999.1 |
| Amino acid sequences of our canonical and alternatively spliced KDM1A |
| accession_id | Protein sequence |
| O60341-1 | MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTPRKKEPPRASPPGGLAEPPGSAGPQAGPTVV PGSATPMETGIAETPEGRRTSRRKRAKVEYREMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGVEGAAFQ SRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEAPYNSDTVLVHRVHSYLERHGLINFGIYKRI KPLPTKKTGKVIIIGSGVSGLAAARQLQSFGMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGNPMAVVSKQVNMELAKIKQKC PLYEANGQAVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQEKHVKDEQIEHWKKIVKTQEELKELLNKMVN LKEKIKELHQQYKEASEVKPPRDITAEFLVKSKHRDLTALCKEYDELAETQGKLEEKLQELEANPPSDVYLSSRDRQILDWHFANLEFAN ATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGCEVIAVNTRSTSQTFIYKCDAVLCTLPLGVL KQQPPAVQFVPPLPEWKTSAVQRMGFGNLNKVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWNLYKAPILLALVAGEAAGIMENISD DVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPITPGPSIPGAPQPIPRLFFAGEHTIRNYPAT |
| O60341-2 | MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTPRKKEPPRASPPGGLAEPPGSAGPQAGPTVV PGSATPMETGIAETPEGRRTSRRKRAKVEYREMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGQAGGLQD DSSGGYGDGQASGVEGAAFQSRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEAPYNSDTVLVH RVHSYLERHGLINFGIYKRIKPLPTKKTGKVIIIGSGVSGLAAARQLQSFGMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGN PMAVVSKQVNMELAKIKQKCPLYEANGQADTVKVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQEKHVKDE QIEHWKKIVKTQEELKELLNKMVNLKEKIKELHQQYKEASEVKPPRDITAEFLVKSKHRDLTALCKEYDELAETQGKLEEKLQELEANPP SDVYLSSRDRQILDWHFANLEFANATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGCEVIAVN TRSTSQTFIYKCDAVLCTLPLGVLKQQPPAVQFVPPLPEWKTSAVQRMGFGNLNKVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWN LYKAPILLALVAGEAAGIMENISDDVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPITPGPSI |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| KDM1A (go to UniProt):O60341 |
| 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 |
| O60341 | Region | 1 | 176 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Substitution;Start=173;End=173 |
| O60341 | Region | 300 | 852 | Note=Demethylase activity | Type=Substitution;Start=369;End=369 |
Gene Isoform Structures and Expression Levels for KDM1A |
| Gene structures of our canonical and alternative spliced genes of KDM1A * 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 O60341-1 |
| 3D view using mol* of O60341-2 |
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 O60341-1 |
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| pLDDT distribution across the protein length of O60341-2 |
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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 O60341-1 |
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| Ramachandran plot of O60341-2 |
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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 |
| O60341-1 | 1.174 | 246 | 1.091 | 346.773 | 0.291 | 0.959 | 1.306 | 1.389 | 1.302 | 1.066 | 0.66 | 14,15,16,284,285,286,287,288,289,307,308,309,310,3 14,315,316,317,329,330,331,332,333,334,335,342,538 ,571,588,589,590,591,624,625,626,629,636,637,659,6 61,751,756,760,761,800,801,802,809,810,811,812,814 |
| O60341-2 | 1.136 | 376 | 1.063 | 865.389 | 0.331 | 0.901 | 1.211 | 1.135 | 1.281 | 0.886 | 0.835 | 304,305,306,307,308,309,327,328,329,330,334,335,33 6,337,349,350,351,352,353,354,355,562,563,564,571, 576,577,578,579,580,582,583,584,588,595,612,613,61 4,615,648,649,650,653,656,660,661,683,685,775,779, 780,781,782,784,785,786,787,788,797,824,825,826,83 0,831,832,833,834,835,836,838 |
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 O60341-1_O60341-1_2iw5_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 O60341-1_2iw5_A_O60341-2.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of O60341-1_O60341-2.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/O60341-1_vs_O60341-2.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/O60341-1_vs_O60341-2.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 KDM1A |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
| O60341 | KDM1A | DB16446 | Vafidemstat | investigational | inhibitor, binder, modulator |
Related Diseases to KDM1A |
| Previous studies relating to the alternative splicing of KDM1A and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| KDM1A | 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 |
| KDM1A | 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 |
| KDM1A | 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 |
| KDM1A | 25904247 | Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. | Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after γ-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease. | D002471 | Cell Transformation, Neoplastic |
| KDM1A | 25904247 | Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. | Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after γ-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease. | D054218 | Precursor T-Cell Lymphoblastic Leukemia-Lymphoma |
Clinically important variants in KDM1A |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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