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Protein

Lysine-specific histone demethylase 1A

Gene

KDM1A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7.6 Publications

Cofactori

FAD2 Publications

Kineticsi

  1. KM=3.0 µM for H3 monomethyl-K41 Publication
  2. KM=4.2 µM for H3 dimethyl-K41 Publication
  3. KM=3.9 µM for H3 monomethyl-K4-monomethyl-K91 Publication
  4. KM=17.5 µM for monomethyl-K4-acetyl-K91 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei289FAD2 Publications1
    Binding sitei308FAD2 Publications1
    Binding sitei310FAD2 Publications1
    Binding sitei316FAD2 Publications1
    Binding sitei801FAD2 Publications1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi281 – 309FADSequence analysisAdd BLAST29
    Nucleotide bindingi332 – 333FAD2 Publications2
    Nucleotide bindingi810 – 811FAD2 Publications2

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionChromatin regulator, Developmental protein, Oxidoreductase, Repressor
    Biological processTranscription, Transcription regulation
    LigandFAD, Flavoprotein

    Enzyme and pathway databases

    BRENDAi1.14.11.B1 2681
    1.14.11.B2 2681
    ReactomeiR-HSA-3214815 HDACs deacetylate histones
    R-HSA-3214842 HDMs demethylate histones
    R-HSA-5625886 Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
    R-HSA-8943724 Regulation of PTEN gene transcription
    R-HSA-9018519 Estrogen-dependent gene expression
    R-HSA-983231 Factors involved in megakaryocyte development and platelet production
    SABIO-RKiO60341
    SIGNORiO60341

    Protein family/group databases

    MoonDBiO60341 Predicted

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Lysine-specific histone demethylase 1A (EC:1.-.-.-)
    Alternative name(s):
    BRAF35-HDAC complex protein BHC110
    Flavin-containing amine oxidase domain-containing protein 2
    Gene namesi
    Name:KDM1A
    Synonyms:AOF2, KDM1, KIAA0601, LSD1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 1

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000004487.15
    HGNCiHGNC:29079 KDM1A
    MIMi609132 gene
    neXtProtiNX_O60341

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Cleft palate, psychomotor retardation, and distinctive facial features (CPRF)3 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA syndrome characterized by cleft palate, developmental delay, psychomotor retardation, and facial dysmorphic features including a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and widely spaced teeth. Cleft palate is a congenital fissure of the soft and/or hard palate, due to faulty fusion.
    See also OMIM:616728
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_076366379E → K in CPRF. 1 PublicationCorresponds to variant dbSNP:rs864309715Ensembl.1
    Natural variantiVAR_076367556D → G in CPRF. 2 PublicationsCorresponds to variant dbSNP:rs864309716Ensembl.1
    Natural variantiVAR_076368761Y → H in CPRF. 2 PublicationsCorresponds to variant dbSNP:rs864309714Ensembl.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi503K → R: Loss of polyubiquitination. 1 Publication1
    Mutagenesisi535N → A: Strongly reduces demethylase activity. 1 Publication1
    Mutagenesisi564H → A: Strongly reduces demethylase activity. 1 Publication1
    Mutagenesisi661K → A: Abolishes histone demethylase activity. 1 Publication1
    Mutagenesisi761Y → A: Strongly reduces demethylase activity. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi23028
    MalaCardsiKDM1A
    MIMi616728 phenotype
    OpenTargetsiENSG00000004487
    PharmGKBiPA165751392

    Chemistry databases

    ChEMBLiCHEMBL6136
    GuidetoPHARMACOLOGYi2669

    Polymorphism and mutation databases

    BioMutaiKDM1A

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000998811 – 852Lysine-specific histone demethylase 1AAdd BLAST852

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei59PhosphothreonineCombined sources1
    Modified residuei104PhosphothreonineCombined sources1
    Modified residuei126PhosphoserineCombined sources1
    Modified residuei131PhosphoserineCombined sources1
    Modified residuei135PhosphotyrosineCombined sources1
    Modified residuei137PhosphoserineCombined sources1
    Modified residuei166PhosphoserineCombined sources1
    Cross-linki442Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Cross-linki469Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Cross-linki503Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Modified residuei611PhosphoserineCombined sources1
    Modified residuei849PhosphoserineCombined sources1

    Post-translational modificationi

    Polyubiquitinated by JADE2; which leads to its proteasomal degradation.1 Publication

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiO60341
    MaxQBiO60341
    PaxDbiO60341
    PeptideAtlasiO60341
    PRIDEiO60341
    ProteomicsDBi49364
    49365 [O60341-2]

    PTM databases

    iPTMnetiO60341
    PhosphoSitePlusiO60341

    Expressioni

    Tissue specificityi

    Ubiquitously expressed.1 Publication

    Inductioni

    Down-regulated during neural differentiation in neuroblastoma cancer.1 Publication

    Gene expression databases

    BgeeiENSG00000004487 Expressed in 233 organ(s), highest expression level in right testis
    CleanExiHS_AOF2
    ExpressionAtlasiO60341 baseline and differential
    GenevisibleiO60341 HS

    Organism-specific databases

    HPAiCAB005884
    HPA053660

    Interactioni

    Subunit structurei

    Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:12032298, PubMed:11102443). Interacts directly with GFI1 and GFI1B. Interacts with INSM1 (By similarity). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763, PubMed:16140033, PubMed:16885027). In the complex, RCOR1/CoREST strongly enhances the demethylase activity and protects it from the proteasome while PHF21A/BHC80 inhibits the demethylase activity (PubMed:16079794, PubMed:16956976). Interacts with the androgen receptor (AR) (PubMed:16079795). Interacts with ASXL1 (PubMed:19880879). Interacts with SNAI1 (via SNAG domain) (PubMed:20562920). Interacts (via AOD/Tower domain) with JADE2 (via C-terminus) (PubMed:25018020). Interacts with ESRRB; co-occupes the core set of ESRRB targets (By similarity).By similarity11 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    AKAP9Q999962EBI-710124,EBI-1048311
    C8orf74Q6P0472EBI-710124,EBI-8466055
    CCDC151A5D8V72EBI-710124,EBI-8466445
    CDCA4Q9BXL82EBI-710124,EBI-1773949
    CEP70Q8NHQ12EBI-710124,EBI-739624
    CHD1O146468EBI-15599570,EBI-1560858
    CHD3Q128734EBI-710124,EBI-523590
    DNAJA3Q96EY12EBI-710124,EBI-356767
    EHMT2Q96KQ72EBI-15599570,EBI-744366
    EHMT2Q96KQ7-13EBI-15599570,EBI-15737402
    FAM9AQ8IZU12EBI-710124,EBI-8468186
    FYCO1Q9BQS82EBI-710124,EBI-2869338
    GSTCDQ8NEC72EBI-710124,EBI-8469616
    GTPBP2Q9BX102EBI-710124,EBI-6115579
    HAUS1Q96CS22EBI-710124,EBI-2514791
    HDAC3O153794EBI-710124,EBI-607682
    HESX1Q9UBX02EBI-710124,EBI-8470369
    HIST3H3Q166952EBI-710124,EBI-358900
    IMMTQ168912EBI-710124,EBI-473801
    KLHDC4Q8TBB52EBI-710124,EBI-8472352
    KRT33BQ145253EBI-710124,EBI-1049638
    LOXL4Q96JB62EBI-710124,EBI-749562
    MBD3O959834EBI-710124,EBI-1783068
    NOTCH1P465318EBI-710124,EBI-636374
    NR1H3Q131332EBI-710124,EBI-781356
    NR2E1Q9Y4662EBI-710124,EBI-11792373
    OFCC1Q8IZS52EBI-710124,EBI-8477661
    PELP1Q8IZL86EBI-710124,EBI-716449
    PHF19Q5T6S32EBI-710124,EBI-2339674
    PPARDQ031812EBI-710124,EBI-6426768
    PRKCBP05771-12EBI-15599570,EBI-5774492
    PSMC1P621912EBI-710124,EBI-357598
    RASSF1Q9NS232EBI-710124,EBI-367363
    RASSF2P507492EBI-710124,EBI-960081
    RBPJQ063304EBI-710124,EBI-632552
    RCOR1Q9UKL06EBI-15599570,EBI-926563
    RCOR2Q8IZ403EBI-710124,EBI-723853
    RCOR3Q9P2K3-24EBI-710124,EBI-1504830
    SAMD3Q8N6K72EBI-710124,EBI-748741
    SERGEFQ9UGK82EBI-710124,EBI-465368
    SF3B2Q134352EBI-710124,EBI-749111
    SMAD9O151982EBI-710124,EBI-748763
    SMARCA4P515323EBI-710124,EBI-302489
    SMARCC1Q929223EBI-710124,EBI-355653
    SNAI1O9586332EBI-710124,EBI-1045459
    SNF8Q96H202EBI-710124,EBI-747719
    SPICE1Q8N0Z33EBI-710124,EBI-2361917
    SPSB1Q96BD62EBI-710124,EBI-2659201
    STX19Q8N4C72EBI-710124,EBI-8484990
    TAL1P175425EBI-15599570,EBI-1753878
    Tal1P220912EBI-15599570,EBI-8006437From Mus musculus.
    TEX9Q8N6V93EBI-710124,EBI-746341
    TP53P046376EBI-15599570,EBI-366083
    TRAF4Q9BUZ43EBI-710124,EBI-3650647
    WASHC3Q9Y3C04EBI-710124,EBI-712969
    ZBED1O960063EBI-710124,EBI-740037

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi116667, 329 interactors
    CORUMiO60341
    DIPiDIP-34641N
    IntActiO60341, 289 interactors
    MINTiO60341
    STRINGi9606.ENSP00000383042

    Chemistry databases

    BindingDBiO60341

    Structurei

    Secondary structure

    1852
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliO60341
    SMRiO60341
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO60341

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini174 – 273SWIRMPROSITE-ProRule annotationAdd BLAST100

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni300 – 852Demethylase activityAdd BLAST553

    Coiled coil

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Coiled coili110 – 151Sequence analysisAdd BLAST42
    Coiled coili428 – 514Sequence analysisAdd BLAST87

    Compositional bias

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Compositional biasi7 – 42Ala-richAdd BLAST36
    Compositional biasi152 – 156Poly-Pro5

    Domaini

    The SWIRM domain may act as an anchor site for a histone tail.1 Publication

    Sequence similaritiesi

    Belongs to the flavin monoamine oxidase family.Curated

    Keywords - Domaini

    Coiled coil

    Phylogenomic databases

    eggNOGiKOG0029 Eukaryota
    KOG0685 Eukaryota
    ENOG410XSNC LUCA
    GeneTreeiENSGT00530000062888
    InParanoidiO60341
    KOiK11450
    OMAiLWLENPK
    OrthoDBiEOG091G04NO
    PhylomeDBiO60341
    TreeFamiTF312972

    Family and domain databases

    Gene3Di1.10.10.10, 1 hit
    3.50.50.60, 2 hits
    InterProiView protein in InterPro
    IPR002937 Amino_oxidase
    IPR036188 FAD/NAD-bd_sf
    IPR017366 Hist_Lys-spec_deMease
    IPR009057 Homeobox-like_sf
    IPR007526 SWIRM
    IPR036388 WH-like_DNA-bd_sf
    PfamiView protein in Pfam
    PF01593 Amino_oxidase, 1 hit
    PF04433 SWIRM, 1 hit
    PIRSFiPIRSF038051 Histone_Lys-demethylase, 1 hit
    SUPFAMiSSF46689 SSF46689, 1 hit
    SSF51905 SSF51905, 3 hits
    PROSITEiView protein in PROSITE
    PS50934 SWIRM, 1 hit

    Sequences (2+)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.iShow all

    Isoform 1 (identifier: O60341-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MLSGKKAAAA AAAAAAAATG TEAGPGTAGG SENGSEVAAQ PAGLSGPAEV
    60 70 80 90 100
    GPGAVGERTP RKKEPPRASP PGGLAEPPGS AGPQAGPTVV PGSATPMETG
    110 120 130 140 150
    IAETPEGRRT SRRKRAKVEY REMDESLANL SEDEYYSEEE RNAKAEKEKK
    160 170 180 190 200
    LPPPPPQAPP EEENESEPEE PSGVEGAAFQ SRLPHDRMTS QEAACFPDII
    210 220 230 240 250
    SGPQQTQKVF LFIRNRTLQL WLDNPKIQLT FEATLQQLEA PYNSDTVLVH
    260 270 280 290 300
    RVHSYLERHG LINFGIYKRI KPLPTKKTGK VIIIGSGVSG LAAARQLQSF
    310 320 330 340 350
    GMDVTLLEAR DRVGGRVATF RKGNYVADLG AMVVTGLGGN PMAVVSKQVN
    360 370 380 390 400
    MELAKIKQKC PLYEANGQAV PKEKDEMVEQ EFNRLLEATS YLSHQLDFNV
    410 420 430 440 450
    LNNKPVSLGQ ALEVVIQLQE KHVKDEQIEH WKKIVKTQEE LKELLNKMVN
    460 470 480 490 500
    LKEKIKELHQ QYKEASEVKP PRDITAEFLV KSKHRDLTAL CKEYDELAET
    510 520 530 540 550
    QGKLEEKLQE LEANPPSDVY LSSRDRQILD WHFANLEFAN ATPLSTLSLK
    560 570 580 590 600
    HWDQDDDFEF TGSHLTVRNG YSCVPVALAE GLDIKLNTAV RQVRYTASGC
    610 620 630 640 650
    EVIAVNTRST SQTFIYKCDA VLCTLPLGVL KQQPPAVQFV PPLPEWKTSA
    660 670 680 690 700
    VQRMGFGNLN KVVLCFDRVF WDPSVNLFGH VGSTTASRGE LFLFWNLYKA
    710 720 730 740 750
    PILLALVAGE AAGIMENISD DVIVGRCLAI LKGIFGSSAV PQPKETVVSR
    760 770 780 790 800
    WRADPWARGS YSYVAAGSSG NDYDLMAQPI TPGPSIPGAP QPIPRLFFAG
    810 820 830 840 850
    EHTIRNYPAT VHGALLSGLR EAGRIADQFL GAMYTLPRQA TPGVPAQQSP

    SM
    Length:852
    Mass (Da):92,903
    Last modified:August 16, 2004 - v2
    Checksum:iA61CEDE51E4E0C1D
    GO
    Isoform 2 (identifier: O60341-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         173-173: G → GQAGGLQDDSSGGYGDGQASG
         369-369: A → ADTVK

    Note: No experimental confirmation available.
    Show »
    Length:876
    Mass (Da):95,155
    Checksum:i966CA72A70F68111
    GO

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    R4GMQ1R4GMQ1_HUMAN
    Lysine-specific histone demethylase...
    KDM1A
    858Annotation score:
    R4GMP9R4GMP9_HUMAN
    Lysine-specific histone demethylase...
    KDM1A
    301Annotation score:

    Sequence cautioni

    The sequence BAA25527 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti78P → Q in AAH40194 (PubMed:15489334).Curated1
    Sequence conflicti405P → H in AAH48134 (PubMed:15489334).Curated1
    Sequence conflicti669V → A in CAD38675 (PubMed:17974005).Curated1
    Sequence conflicti814A → V in AAH16639 (PubMed:15489334).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_076366379E → K in CPRF. 1 PublicationCorresponds to variant dbSNP:rs864309715Ensembl.1
    Natural variantiVAR_076367556D → G in CPRF. 2 PublicationsCorresponds to variant dbSNP:rs864309716Ensembl.1
    Natural variantiVAR_076368761Y → H in CPRF. 2 PublicationsCorresponds to variant dbSNP:rs864309714Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_011198173G → GQAGGLQDDSSGGYGDGQAS G in isoform 2. 1 Publication1
    Alternative sequenceiVSP_011199369A → ADTVK in isoform 2. 1 Publication1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AB011173 mRNA Translation: BAA25527.1 Different initiation.
    AL031428 Genomic DNA No translation available.
    BC016639 mRNA Translation: AAH16639.1
    BC025362 mRNA Translation: AAH25362.1
    BC040194 mRNA Translation: AAH40194.3
    BC048134 mRNA Translation: AAH48134.2
    AL833812 mRNA Translation: CAD38675.2
    CCDSiCCDS30627.1 [O60341-1]
    CCDS53278.1 [O60341-2]
    RefSeqiNP_001009999.1, NM_001009999.2 [O60341-2]
    NP_055828.2, NM_015013.3 [O60341-1]
    UniGeneiHs.591518

    Genome annotation databases

    EnsembliENST00000356634; ENSP00000349049; ENSG00000004487 [O60341-1]
    ENST00000400181; ENSP00000383042; ENSG00000004487 [O60341-2]
    GeneIDi23028
    KEGGihsa:23028
    UCSCiuc001bgi.3 human [O60341-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Entry informationi

    Entry nameiKDM1A_HUMAN
    AccessioniPrimary (citable) accession number: O60341
    Secondary accession number(s): A8MWP9
    , Q5TH94, Q5TH95, Q86VT7, Q8IXK4, Q8NDP6, Q8TAZ3, Q96AW4
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 16, 2004
    Last sequence update: August 16, 2004
    Last modified: September 12, 2018
    This is version 191 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health

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