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Q63943

- MEF2D_MOUSE

UniProt

Q63943 - MEF2D_MOUSE

Protein

Myocyte-specific enhancer factor 2D

Gene

Mef2d

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 116 (01 Oct 2014)
      Sequence version 2 (27 Jul 2011)
      Previous versions | rss
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    Functioni

    Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT]4TAR-3', found in numerous muscle-specific, growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. Plays a critical role in the regulation of neuronal apoptosis.2 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei288 – 2892CleavageCurated

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi58 – 8629Mef2-typeSequence AnalysisAdd
    BLAST

    GO - Molecular functioni

    1. DNA binding Source: MGI
    2. enzyme binding Source: BHF-UCL
    3. protein heterodimerization activity Source: UniProtKB
    4. protein homodimerization activity Source: UniProtKB
    5. RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
    6. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: NTNU_SB
    7. sequence-specific DNA binding transcription factor activity Source: MGI

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. chondrocyte differentiation Source: MGI
    3. endochondral ossification Source: MGI
    4. nervous system development Source: UniProtKB-KW
    5. osteoblast differentiation Source: MGI
    6. positive regulation of transcription, DNA-templated Source: MGI
    7. positive regulation of transcription from RNA polymerase II promoter Source: NTNU_SB
    8. regulation of transcription, DNA-templated Source: MGI
    9. skeletal muscle cell differentiation Source: MGI

    Keywords - Molecular functioni

    Activator, Developmental protein

    Keywords - Biological processi

    Apoptosis, Differentiation, Neurogenesis, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Myocyte-specific enhancer factor 2D
    Gene namesi
    Name:Mef2d
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 3

    Organism-specific databases

    MGIiMGI:99533. Mef2d.

    Subcellular locationi

    Nucleus 1 PublicationPROSITE-ProRule annotation
    Note: Translocated by HDAC4 to nuclear dots.By similarity

    GO - Cellular componenti

    1. nucleus Source: MGI

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi20 – 201T → A: No change in DNA-binding activity. 1 Publication
    Mutagenesisi20 – 201T → D: Dramatic decrease in DNA-binding. 1 Publication
    Mutagenesisi121 – 1211S → A: Abolishes phosphorylation by PKA. No change in protein levels. Loss of protein stability on PKA stimulation. Loss of PKA-mediated repression. No change in interaction with HDAC4 in response to PKA; when associated with A-190. 1 Publication
    Mutagenesisi190 – 1901S → A: Abolishes phosphorylation by PKA. No change in protein levels. Loss of protein stability on PKA stimulation mediated repression. No change in interaction with HDAC4 in response to PKA; when associated with A-121. 1 Publication
    Mutagenesisi437 – 4371S → A: Loss of calpain/Cdk5-mediated neuron apoptosis. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 514514Myocyte-specific enhancer factor 2DPRO_0000199436Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei121 – 1211Phosphoserine; by PKA1 Publication
    Modified residuei180 – 1801Phosphoserine; by MAPK7By similarity
    Modified residuei190 – 1901Phosphoserine; by PKA1 Publication
    Modified residuei231 – 2311PhosphoserineBy similarity
    Modified residuei245 – 2451N6-acetyllysineBy similarity
    Modified residuei251 – 2511Phosphoserine1 Publication
    Modified residuei432 – 4321N6-acetyllysine; alternateBy similarity
    Cross-linki432 – 432Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternateBy similarity
    Modified residuei437 – 4371Phosphoserine1 Publication

    Post-translational modificationi

    Phosphorylated on Ser-437 is which is required for Lys-432 sumoylation and inhibits transcriptional activity. Phosphorylation on this residue by CDK5 is dependent on p35 and calpains. Phosphorylated by PKA at Ser-121 and Ser-190 represses transcriptional activity in embryonic and postnatal skeletal muscle, and stabilizes protein levels. No in vitro phosphorylation by PKA on Thr-20. Phosphorylated and activated by CaMK4 By similarity.By similarity
    Acetylated on Lys-432 by CREBBP. Deacetylated by SIRT1 By similarity.By similarity
    Sumoylated on Lys-432 with SUMO2 but not SUMO1; which inhibits transcriptional activity and myogenic activity. Desumoylated by SENP3 By similarity.By similarity
    Proteolytically cleaved in cerebellar granule neurons by caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiQ63943.
    PRIDEiQ63943.

    PTM databases

    PhosphoSiteiQ63943.

    Miscellaneous databases

    PMAP-CutDBQ63943.

    Expressioni

    Tissue specificityi

    Widely expressed though mainly restricted to skeletal and cardiac muscle, brain, neurons and lymphocytes. Differentially expressed depending on if isoforms contain the beta domain or not, with the total expression of the beta domain-lacking isoforms vastly exceding that of the beta domain-containing isoforms. Isoforms containing the beta domain are expressed primarily in skeletal and cardiac muscle and in brain. Also present in lung and testis. Splicing to include the beta domain is induced in differentiating myocytes. Isoforms lacking the beta domain are expressed less abundantly in skeletal muscle, brain and lymphocytes, and are uniquely found in ovary, liver, spleen and kidney. In embryos, the beta domain-containing and beta domain-lacking isoforms are equally expressed. Also expressed cerebellar granule neurons and other regions of the CNS. Highest levels in the olfactory bulb, cortex, hippocampus, thalamus and cerebellum.3 Publications

    Developmental stagei

    In the developing cerebellum, increasing levels after birth. The majority of this increase occurs around postnataL day 9 reaching a peak at postnatal day 15-18 which is maintained in adults.1 Publication

    Gene expression databases

    ArrayExpressiQ63943.
    BgeeiQ63943.
    CleanExiMM_MEF2D.
    GenevestigatoriQ63943.

    Interactioni

    Subunit structurei

    Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with HDAC4 (in undifferentiating cells); the interaction translocates MEF2D to nuclear dots. Forms a heterodimer with MEF2A By similarity. Interacts with MAPK7; the interaction phosphorylates but does not activate MEF2D. Interacts with MYOG.By similarity2 Publications

    Protein-protein interaction databases

    IntActiQ63943. 4 interactions.
    MINTiMINT-1618951.

    Structurei

    3D structure databases

    ProteinModelPortaliQ63943.
    SMRiQ63943. Positions 2-73.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini3 – 5755MADS-boxPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni286 – 2927Beta domainBy similarity

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi3 – 3129Arg/Lys-rich (basic)Add
    BLAST
    Compositional biasi252 – 2554Poly-Pro
    Compositional biasi365 – 40238Gln/Pro-richAdd
    BLAST
    Compositional biasi444 – 4496Poly-Pro

    Sequence similaritiesi

    Belongs to the MEF2 family.Curated
    Contains 1 MADS-box domain.PROSITE-ProRule annotation
    Contains 1 Mef2-type DNA-binding domain.Curated

    Phylogenomic databases

    eggNOGiCOG5068.
    GeneTreeiENSGT00390000011828.
    HOGENOMiHOG000230620.
    HOVERGENiHBG053944.
    InParanoidiQ63943.
    KOiK09262.
    OMAiHHLNNAQ.

    Family and domain databases

    InterProiIPR022102. HJURP_C.
    IPR002100. TF_MADSbox.
    [Graphical view]
    PfamiPF12347. HJURP_C. 1 hit.
    PF00319. SRF-TF. 1 hit.
    [Graphical view]
    PRINTSiPR00404. MADSDOMAIN.
    SMARTiSM00432. MADS. 1 hit.
    [Graphical view]
    SUPFAMiSSF55455. SSF55455. 1 hit.
    PROSITEiPS00350. MADS_BOX_1. 1 hit.
    PS50066. MADS_BOX_2. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform Non-muscle (identifier: Q63943-1) [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

    MGRKKIQIQR ITDERNRQVT FTKRKFGLMK KAYELSVLCD CEIALIIFNH    50
    SNKLFQYAST DMDKVLLKYT EYNEPHESRT NADIIETLRK KGFNGCDSPE 100
    PDGEDSLEQS PLLEDKYRRA SEELDGLFRR YGSSVPAPNF AMPVTVPVSN 150
    QSSMQFSNPS SSLVTPSLVT SSLTDPRLLS PQQPALQRNS VSPGLPQRPA 200
    SAGAMLGGDL NSANGACPSP VGNGYVSARA SPGLLPVANG NSLNKVIPAK 250
    SPPPPTHNTQ LGAPSRKPDL RVITSQGGKG LMHHLTEDHL DLNNAQRLGV 300
    SQSTHSLTTP VVSVATPSLL SQGLPFSSMP TAYNTDYQLP SAELSSLPAF 350
    SSPAGLALGN VTAWQQPQPP QQPQPPQPPQ SQPQPPQPQP QQPPQQQPHL 400
    VPVSLSNLIP GSPLPHVGAA LTVTTHPHIS IKSEPVSPSR ERSPAPPPPA 450
    VFPAARPEPG EGLSSPAGGS YETGDRDDGR GDFGPTLGLL RPAPEPEAEG 500
    SAVKRMRLDT WTLK 514
    Length:514
    Mass (Da):55,065
    Last modified:July 27, 2011 - v2
    Checksum:i34833264CE22C63F
    GO
    Isoform Muscle (identifier: Q63943-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         87-132: TLRKKGFNGC...ELDGLFRRYG → ALHNNDRECE...DKMMQSYRLA
         286-292: Missing.

    Show »
    Length:514
    Mass (Da):55,350
    Checksum:iB823D233F0492DE0
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti287 – 2871E → G in AAB29973. (PubMed:8114702)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei87 – 13246TLRKK…FRRYG → ALHNNDRECESPEVDEAFAL TPQTEEKYKKIDEEKYKKID EEFDKMMQSYRLA in isoform Muscle. 1 PublicationVSP_006253Add
    BLAST
    Alternative sequencei286 – 2927Missing in isoform Muscle. 1 PublicationVSP_006254

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S68893 mRNA. Translation: AAB29973.1.
    S68895 mRNA. Translation: AAB29974.1.
    AC137525 Genomic DNA. No translation available.
    PIRiB56201.
    RefSeqiXP_006501152.1. XM_006501089.1. [Q63943-1]
    UniGeneiMm.28184.
    Mm.485397.

    Genome annotation databases

    EnsembliENSMUST00000107559; ENSMUSP00000103184; ENSMUSG00000001419. [Q63943-1]
    GeneIDi17261.
    KEGGimmu:17261.
    UCSCiuc008pua.1. mouse. [Q63943-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S68893 mRNA. Translation: AAB29973.1 .
    S68895 mRNA. Translation: AAB29974.1 .
    AC137525 Genomic DNA. No translation available.
    PIRi B56201.
    RefSeqi XP_006501152.1. XM_006501089.1. [Q63943-1 ]
    UniGenei Mm.28184.
    Mm.485397.

    3D structure databases

    ProteinModelPortali Q63943.
    SMRi Q63943. Positions 2-73.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi Q63943. 4 interactions.
    MINTi MINT-1618951.

    PTM databases

    PhosphoSitei Q63943.

    Proteomic databases

    PaxDbi Q63943.
    PRIDEi Q63943.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000107559 ; ENSMUSP00000103184 ; ENSMUSG00000001419 . [Q63943-1 ]
    GeneIDi 17261.
    KEGGi mmu:17261.
    UCSCi uc008pua.1. mouse. [Q63943-1 ]

    Organism-specific databases

    CTDi 4209.
    MGIi MGI:99533. Mef2d.

    Phylogenomic databases

    eggNOGi COG5068.
    GeneTreei ENSGT00390000011828.
    HOGENOMi HOG000230620.
    HOVERGENi HBG053944.
    InParanoidi Q63943.
    KOi K09262.
    OMAi HHLNNAQ.

    Miscellaneous databases

    ChiTaRSi MEF2D. mouse.
    PMAP-CutDB Q63943.
    PROi Q63943.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q63943.
    Bgeei Q63943.
    CleanExi MM_MEF2D.
    Genevestigatori Q63943.

    Family and domain databases

    InterProi IPR022102. HJURP_C.
    IPR002100. TF_MADSbox.
    [Graphical view ]
    Pfami PF12347. HJURP_C. 1 hit.
    PF00319. SRF-TF. 1 hit.
    [Graphical view ]
    PRINTSi PR00404. MADSDOMAIN.
    SMARTi SM00432. MADS. 1 hit.
    [Graphical view ]
    SUPFAMi SSF55455. SSF55455. 1 hit.
    PROSITEi PS00350. MADS_BOX_1. 1 hit.
    PS50066. MADS_BOX_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing."
      Martin J.F., Miano J.M., Hustad C.M., Copeland N.G., Jenkins N.A., Olson E.N.
      Mol. Cell. Biol. 14:1647-1656(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MUSCLE AND NON-MUSCLE).
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: C57BL/6J.
    3. "The expression of MEF2 genes is implicated in CNS neuronal differentiation."
      Lin X., Shah S., Bulleit R.F.
      Brain Res. Mol. Brain Res. 42:307-316(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
      Tissue: Cerebellum.
    4. "Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain."
      Zhu B., Ramachandran B., Gulick T.
      J. Biol. Chem. 280:28749-28760(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY OF ISOFORMS.
    5. "Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications."
      Zhao X., Sternsdorf T., Bolger T.A., Evans R.M., Yao T.-P.
      Mol. Cell. Biol. 25:8456-8464(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION.
    6. "Skeletal muscle specification by myogenin and Mef2D via the SWI/SNF ATPase Brg1."
      Ohkawa Y., Marfella C.G., Imbalzano A.N.
      EMBO J. 25:490-501(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MYOG.
    7. "Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2."
      Smith P.D., Mount M.P., Shree R., Callaghan S., Slack R.S., Anisman H., Vincent I., Wang X., Mao Z., Park D.S.
      J. Neurosci. 26:440-447(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-437, FUNCTION, TISSUE SPECIFICITY, MUTAGENESIS OF SER-437.
    8. "Protein kinase A represses skeletal myogenesis by targeting myocyte enhancer factor 2D."
      Du M., Perry R.L.S., Nowacki N.B., Gordon J.W., Salma J., Zhao J., Aziz A., Chan J., Siu K.W.M., McDermott J.C.
      Mol. Cell. Biol. 28:2952-2970(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-121 AND SER-190, INTERACTION WITH HDAC4, FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF THR-20; SER-121 AND SER-190.
    9. "Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
      Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
      Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Embryonic fibroblast.

    Entry informationi

    Entry nameiMEF2D_MOUSE
    AccessioniPrimary (citable) accession number: Q63943
    Secondary accession number(s): E9QKS9, Q63944
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1997
    Last sequence update: July 27, 2011
    Last modified: October 1, 2014
    This is version 116 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3