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Protein

O-acetyl-ADP-ribose deacetylase MACROD1

Gene

MACROD1

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

Functioni

Removes ADP-ribose from glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins. Plays a role in estrogen signaling. Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen. May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation. Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction. Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells. Enhances ESR1-mediated transcription activity.6 Publications

Miscellaneous

Overexpression may promote MCF-7 cells proliferation. There is an approximate one-third increase of the invasive capacity of MACROD1-overexpressing cells. The expression of CDH1 is repressed by MACROD1. Further analyzes demonstrats that MACROD1 inhibits CDH1 transactivation in a dose dependent manner. Inhibition is abolished by estrogen deprivation, indicating that the down-regulation of CDH1 transcription by MACROD1 requires ESR1 mediation. Binding of ESR1 to the CDH1 promoter is antagonized by MACROD1, suggesting that MACROD1 could interfere with ESR1-mediated transcription. Knockdown of MACROD1 leads to impaired AR function and greatly attenuates the coactivation of AR by other AR coactivators such as UXT and NCOA1. This interference also markedly inhibits the androgen-stimulated proliferation of androgen-sensitive LNCaP prostate cancer cells. MACROD1 knockdown does not significantly affect the growth rate of AR-negative PC-3 prostate cancer cells.

Enzyme regulationi

Subject to competitive inhibition by the product ADP-ribose.1 Publication

Kineticsi

  1. KM=373 µM for O-acetyl-ADP-ribose1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei306SubstrateBy similarity1

    GO - Molecular functioni

    • deacetylase activity Source: UniProtKB
    • hydrolase activity, acting on glycosyl bonds Source: UniProtKB

    GO - Biological processi

    • cellular response to DNA damage stimulus Source: UniProtKB
    • protein de-ADP-ribosylation Source: UniProtKB
    • purine nucleoside metabolic process Source: UniProtKB

    Keywordsi

    Molecular functionHydrolase
    Biological processDNA damage

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    O-acetyl-ADP-ribose deacetylase MACROD1 (EC:3.2.2.-, EC:3.5.1.-)
    Alternative name(s):
    MACRO domain-containing protein 1
    Protein LRP16
    [Protein ADP-ribosylglutamate] hydrolase
    Gene namesi
    Name:MACROD1
    Synonyms:LRP16
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 11

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000133315.10
    HGNCiHGNC:29598 MACROD1
    MIMi610400 gene
    neXtProtiNX_Q9BQ69

    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

    A chromosomal aberration involving MACROD1 is found in acute leukemia. Translocation t(11;21)(q13;q22) that forms a RUNX1-MACROD1 fusion protein.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi160D → A: Reduced enzyme activity. 1 Publication1
    Mutagenesisi167D → A: Reduced enzyme activity. 1 Publication1
    Mutagenesisi171N → A: Reduced enzyme activity. No significant effect on affinity for substrate. 1 Publication1
    Mutagenesisi174N → A: Slightly reduced ADP-ribosyl hydrolase activity; when associated with A-184. Reduces O-acetyl-ADP-ribose deacetylase activity by 93%; when associated with A-184. No significant effect on affinity for substrate. 2 Publications1
    Mutagenesisi184D → A: Slightly reduced ADP-ribosyl hydrolase activity; when associated with A-174. Reduces O-acetyl-ADP-ribose deacetylase activity by 93%; when associated with A-174. No significant effect on affinity for substrate. 2 Publications1
    Mutagenesisi188H → A: Reduced enzyme activity. 1 Publication1
    Mutagenesisi268S → A: No significant effect on enzyme activity. 1 Publication1
    Mutagenesisi270G → E: Loss of enzyme activity. 2 Publications1

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sitei100Breakpoint for translocation to form RUNX1-MACROD11 Publication1

    Organism-specific databases

    DisGeNETi28992
    OpenTargetsiENSG00000133315
    PharmGKBiPA162394816

    Polymorphism and mutation databases

    BioMutaiMACROD1
    DMDMi32129719

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000844851 – 325O-acetyl-ADP-ribose deacetylase MACROD1Add BLAST325

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei96N6-succinyllysineBy similarity1
    Modified residuei103N6-succinyllysineBy similarity1
    Modified residuei129N6-succinyllysineBy similarity1
    Cross-linki138Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Modified residuei163N6-acetyllysineBy similarity1

    Keywords - PTMi

    Acetylation, Isopeptide bond, Ubl conjugation

    Proteomic databases

    EPDiQ9BQ69
    MaxQBiQ9BQ69
    PaxDbiQ9BQ69
    PeptideAtlasiQ9BQ69
    PRIDEiQ9BQ69

    PTM databases

    iPTMnetiQ9BQ69
    PhosphoSitePlusiQ9BQ69

    Expressioni

    Inductioni

    Overexpressed by estrogens in breast cancer MCF-7 cells, probably via an activation of nuclear receptors for steroids (ESR1 but not ESR2). Significantly increased by estrogens in ESR1-positive Ishikawa endometrial cancer cells. Up-regulated in 17-beta-estradiol-responsive BG-1 ovarian cancer cells but down-regulated in estrogen-resistant SKOV3 ovarian cancer cells. Induced by androgen.4 Publications

    Gene expression databases

    BgeeiENSG00000133315
    CleanExiHS_MACROD1
    GenevisibleiQ9BQ69 HS

    Organism-specific databases

    HPAiHPA041031
    HPA071075

    Interactioni

    Subunit structurei

    Interacts with ESR1; Interacts in a manner that is estrogen independent but is enhanced by estrogen. Interacts (via macro domain) with AR.2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ESR1P033724EBI-5324932,EBI-78473

    Protein-protein interaction databases

    BioGridi118813, 31 interactors
    IntActiQ9BQ69, 3 interactors
    STRINGi9606.ENSP00000255681

    Structurei

    Secondary structure

    1325
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi94 – 103Combined sources10
    Helixi107 – 110Combined sources4
    Helixi111 – 113Combined sources3
    Helixi122 – 124Combined sources3
    Helixi128 – 132Combined sources5
    Helixi148 – 151Combined sources4
    Beta strandi154 – 159Combined sources6
    Helixi161 – 163Combined sources3
    Beta strandi164 – 172Combined sources9
    Helixi182 – 191Combined sources10
    Helixi193 – 200Combined sources8
    Beta strandi210 – 214Combined sources5
    Beta strandi218 – 227Combined sources10
    Helixi237 – 256Combined sources20
    Beta strandi261 – 264Combined sources4
    Helixi276 – 294Combined sources19
    Helixi295 – 297Combined sources3
    Beta strandi299 – 305Combined sources7
    Helixi308 – 321Combined sources14

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2X47X-ray1.70A91-325[»]
    ProteinModelPortaliQ9BQ69
    SMRiQ9BQ69
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9BQ69

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini141 – 322MacroPROSITE-ProRule annotationAdd BLAST182

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni159 – 161Substrate bindingBy similarity3
    Regioni172 – 174Substrate bindingBy similarity3
    Regioni179 – 184Substrate bindingBy similarity6
    Regioni267 – 273Substrate bindingCurated7

    Phylogenomic databases

    eggNOGiKOG2633 Eukaryota
    COG2110 LUCA
    GeneTreeiENSGT00520000055566
    HOGENOMiHOG000086960
    HOVERGENiHBG052356
    InParanoidiQ9BQ69
    OMAiKITCGYR
    OrthoDBiEOG091G0NNH
    PhylomeDBiQ9BQ69
    TreeFamiTF341440

    Family and domain databases

    InterProiView protein in InterPro
    IPR002589 Macro_dom
    PfamiView protein in Pfam
    PF01661 Macro, 1 hit
    SMARTiView protein in SMART
    SM00506 A1pp, 1 hit
    PROSITEiView protein in PROSITE
    PS51154 MACRO, 1 hit

    Sequencei

    Sequence statusi: Complete.

    Q9BQ69-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSLQSRLSGR LAQLRAAGQL LVPPRPRPGH LAGATRTRSS TCGPPAFLGV
    60 70 80 90 100
    FGRRARTSAG VGAWGAAAVG RTAGVRTWAP LAMAAKVDLS TSTDWKEAKS
    110 120 130 140 150
    FLKGLSDKQR EEHYFCKDFV RLKKIPTWKE MAKGVAVKVE EPRYKKDKQL
    160 170 180 190 200
    NEKISLLRSD ITKLEVDAIV NAANSSLLGG GGVDGCIHRA AGPLLTDECR
    210 220 230 240 250
    TLQSCKTGKA KITGGYRLPA KYVIHTVGPI AYGEPSASQA AELRSCYLSS
    260 270 280 290 300
    LDLLLEHRLR SVAFPCISTG VFGYPCEAAA EIVLATLREW LEQHKDKVDR
    310 320
    LIICVFLEKD EDIYRSRLPH YFPVA
    Length:325
    Mass (Da):35,505
    Last modified:June 16, 2003 - v2
    Checksum:i82294BFC904FA4D0
    GO

    Sequence cautioni

    The sequence AAH03188 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence AAH03188 differs from that shown. Reason: Erroneous initiation.Curated

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF202922 mRNA Translation: AAF15294.2
    BC000270 mRNA Translation: AAH00270.2
    BC003188 mRNA Translation: AAH03188.1 Different initiation.
    BC007297 mRNA Translation: AAH07297.1
    BC008316 mRNA Translation: AAH08316.1
    CCDSiCCDS8056.1
    RefSeqiNP_054786.2, NM_014067.3
    UniGeneiHs.602898

    Genome annotation databases

    EnsembliENST00000255681; ENSP00000255681; ENSG00000133315
    GeneIDi28992
    KEGGihsa:28992
    UCSCiuc001nyh.4 human

    Keywords - Coding sequence diversityi

    Chromosomal rearrangement

    Similar proteinsi

    Entry informationi

    Entry nameiMACD1_HUMAN
    AccessioniPrimary (citable) accession number: Q9BQ69
    Secondary accession number(s): Q9UH96
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 16, 2003
    Last sequence update: June 16, 2003
    Last modified: May 23, 2018
    This is version 131 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, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references

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