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Q63943

- MEF2D_MOUSE

UniProt

Q63943 - MEF2D_MOUSE

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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

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 – 2892Cleavage Inferred

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi58 – 8629Mef2-type Reviewed prediction
Add
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. 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 from RNA polymerase II promoter Source: MGI
  7. positive regulation of transcription, DNA-templated Source: MGI
  8. regulation of transcription, DNA-templated Source: MGI
  9. skeletal muscle cell differentiation Source: MGI
  10. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

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
Note: Translocated by HDAC4 to nuclear dots By similarity.1 Publication

GO - Cellular componenti

  1. nucleus Source: MGI
Complete GO annotation...

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 2D
PRO_0000199436Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei121 – 1211Phosphoserine; by PKA1 Publication
Modified residuei180 – 1801Phosphoserine; by MAPK7 By similarity
Modified residuei190 – 1901Phosphoserine; by PKA1 Publication
Modified residuei231 – 2311Phosphoserine By similarity
Modified residuei245 – 2451N6-acetyllysine By similarity
Modified residuei251 – 2511Phosphoserine1 Publication
Modified residuei432 – 4321N6-acetyllysine; alternate By similarity
Cross-linki432 – 432Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate By 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.2 Publications
Acetylated on Lys-432 by CREBBP. Deacetylated by SIRT1 By similarity.
Sumoylated on Lys-432 with SUMO2 but not SUMO1; which inhibits transcriptional activity and myogenic activity. Desumoylated by SENP3 By similarity.1 Publication
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.2 Publications

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.2 Publications

Protein-protein interaction databases

IntActiQ63943. 4 interactions.
MINTiMINT-1618951.

Structurei

3D structure databases

ProteinModelPortaliQ63943.
SMRiQ63943. Positions 2-73.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini3 – 5755MADS-box
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni286 – 2927Beta domain By 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-rich
Add
BLAST
Compositional biasi444 – 4496Poly-Pro

Sequence similaritiesi

Belongs to the MEF2 family.
Contains 1 MADS-box domain.

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

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei87 – 13246TLRKK…FRRYG → ALHNNDRECESPEVDEAFAL TPQTEEKYKKIDEEKYKKID EEFDKMMQSYRLA in isoform Muscle.
VSP_006253Add
BLAST
Alternative sequencei286 – 2927Missing in isoform Muscle.
VSP_006254

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti287 – 2871E → G in AAB29973. 1 Publication

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

« Hide 'large scale' publications
  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: June 11, 2014
This is version 115 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

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