MEF2D_MOUSE
ID MEF2D_MOUSE Reviewed; 514 AA.
AC Q63943; E9QKS9; Q63944;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=Myocyte-specific enhancer factor 2D;
GN Name=Mef2d;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MUSCLE AND NON-MUSCLE).
RX PubMed=8114702; DOI=10.1128/mcb.14.3.1647-1656.1994;
RA Martin J.F., Miano J.M., Hustad C.M., Copeland N.G., Jenkins N.A.,
RA Olson E.N.;
RT "A Mef2 gene that generates a muscle-specific isoform via alternative mRNA
RT splicing.";
RL Mol. Cell. Biol. 14:1647-1656(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Cerebellum;
RX PubMed=9013788; DOI=10.1016/s0169-328x(96)00135-0;
RA Lin X., Shah S., Bulleit R.F.;
RT "The expression of MEF2 genes is implicated in CNS neuronal
RT differentiation.";
RL Brain Res. Mol. Brain Res. 42:307-316(1996).
RN [4]
RP TISSUE SPECIFICITY OF ISOFORMS.
RX PubMed=15834131; DOI=10.1074/jbc.m502491200;
RA Zhu B., Ramachandran B., Gulick T.;
RT "Alternative pre-mRNA splicing governs expression of a conserved acidic
RT transactivation domain in myocyte enhancer factor 2 factors of striated
RT muscle and brain.";
RL J. Biol. Chem. 280:28749-28760(2005).
RN [5]
RP SUMOYLATION.
RX PubMed=16166628; DOI=10.1128/mcb.25.19.8456-8464.2005;
RA Zhao X., Sternsdorf T., Bolger T.A., Evans R.M., Yao T.-P.;
RT "Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-
RT mediated lysine modifications.";
RL Mol. Cell. Biol. 25:8456-8464(2005).
RN [6]
RP INTERACTION WITH MYOG.
RX PubMed=16424906; DOI=10.1038/sj.emboj.7600943;
RA Ohkawa Y., Marfella C.G., Imbalzano A.N.;
RT "Skeletal muscle specification by myogenin and Mef2D via the SWI/SNF ATPase
RT Brg1.";
RL EMBO J. 25:490-501(2006).
RN [7]
RP PHOSPHORYLATION AT SER-437, FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS
RP OF SER-437.
RX PubMed=16407541; DOI=10.1523/jneurosci.2875-05.2006;
RA Smith P.D., Mount M.P., Shree R., Callaghan S., Slack R.S., Anisman H.,
RA Vincent I., Wang X., Mao Z., Park D.S.;
RT "Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron
RT death through modulation of the transcription factor myocyte enhancer
RT factor 2.";
RL J. Neurosci. 26:440-447(2006).
RN [8]
RP PHOSPHORYLATION AT SER-121 AND SER-190, INTERACTION WITH HDAC4, FUNCTION,
RP SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS
RP OF THR-20; SER-121 AND SER-190.
RX PubMed=18299387; DOI=10.1128/mcb.00248-08;
RA Du M., Perry R.L.S., Nowacki N.B., Gordon J.W., Salma J., Zhao J., Aziz A.,
RA Chan J., Siu K.W.M., McDermott J.C.;
RT "Protein kinase A represses skeletal myogenesis by targeting myocyte
RT enhancer factor 2D.";
RL Mol. Cell. Biol. 28:2952-2970(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200;
RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.;
RT "Large scale localization of protein phosphorylation by use of electron
RT capture dissociation mass spectrometry.";
RL Mol. Cell. Proteomics 8:904-912(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-98; SER-106; SER-110 AND
RP SER-231, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-97 AND THR-107
RP (ISOFORM MUSCLE), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Transcriptional activator which binds specifically to the
CC MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific,
CC growth factor- and stress-induced genes. Mediates cellular functions
CC not only in skeletal and cardiac muscle development, but also in
CC neuronal differentiation and survival. Plays diverse roles in the
CC control of cell growth, survival and apoptosis via p38 MAPK signaling
CC in muscle-specific and/or growth factor-related transcription. Plays a
CC critical role in the regulation of neuronal apoptosis.
CC {ECO:0000269|PubMed:16407541, ECO:0000269|PubMed:18299387}.
CC -!- SUBUNIT: Forms a complex with class II HDACs in undifferentiating
CC cells. On myogenic differentiation, HDACs are released into the
CC cytoplasm allowing MEF2s to interact with other proteins for
CC activation. Interacts with HDAC4 (in undifferentiating cells); the
CC interaction translocates MEF2D to nuclear dots. Forms a heterodimer
CC with MEF2A (By similarity). Interacts with MAPK7; the interaction
CC phosphorylates but does not activate MEF2D (By similarity). Interacts
CC with MYOG. Interacts with CCAR2 and HDAC3 (By similarity).
CC {ECO:0000250|UniProtKB:O89038, ECO:0000250|UniProtKB:Q14814,
CC ECO:0000269|PubMed:16424906, ECO:0000269|PubMed:18299387}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00251,
CC ECO:0000269|PubMed:18299387}. Note=Translocated by HDAC4 to nuclear
CC dots. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Non-muscle;
CC IsoId=Q63943-1; Sequence=Displayed;
CC Name=Muscle;
CC IsoId=Q63943-2; Sequence=VSP_006253, VSP_006254;
CC -!- TISSUE SPECIFICITY: Widely expressed though mainly restricted to
CC skeletal and cardiac muscle, brain, neurons and lymphocytes.
CC Differentially expressed depending on if isoforms contain the beta
CC domain or not, with the total expression of the beta domain-lacking
CC isoforms vastly exceding that of the beta domain-containing isoforms.
CC Isoforms containing the beta domain are expressed primarily in skeletal
CC and cardiac muscle and in brain. Also present in lung and testis.
CC Splicing to include the beta domain is induced in differentiating
CC myocytes. Isoforms lacking the beta domain are expressed less
CC abundantly in skeletal muscle, brain and lymphocytes, and are uniquely
CC found in ovary, liver, spleen and kidney. In embryos, the beta domain-
CC containing and beta domain-lacking isoforms are equally expressed. Also
CC expressed cerebellar granule neurons and other regions of the CNS.
CC Highest levels in the olfactory bulb, cortex, hippocampus, thalamus and
CC cerebellum. {ECO:0000269|PubMed:15834131, ECO:0000269|PubMed:16407541,
CC ECO:0000269|PubMed:9013788}.
CC -!- DEVELOPMENTAL STAGE: In the developing cerebellum, increasing levels
CC after birth. The majority of this increase occurs around postnataL day
CC 9 reaching a peak at postnatal day 15-18 which is maintained in adults.
CC {ECO:0000269|PubMed:9013788}.
CC -!- PTM: Phosphorylated on Ser-437 is which is required for Lys-432
CC sumoylation and inhibits transcriptional activity. Phosphorylation on
CC this residue by CDK5 is dependent on p35 and calpains. Phosphorylated
CC by PKA at Ser-121 and Ser-190 represses transcriptional activity in
CC embryonic and postnatal skeletal muscle, and stabilizes protein levels.
CC No in vitro phosphorylation by PKA on Thr-20. Phosphorylated and
CC activated by CaMK4 (By similarity). {ECO:0000250}.
CC -!- PTM: Acetylated on Lys-432 by CREBBP. Acetylated by EP300. Deacetylated
CC by SIRT1 and HDAC3 (By similarity). {ECO:0000250|UniProtKB:Q14814}.
CC -!- PTM: Sumoylated on Lys-432 with SUMO2 but not SUMO1; which inhibits
CC transcriptional activity and myogenic activity. Desumoylated by SENP3
CC (By similarity). {ECO:0000250}.
CC -!- PTM: Proteolytically cleaved in cerebellar granule neurons by caspase 7
CC following neurotoxicity. Preferentially cleaves the CDK5-mediated
CC hyperphosphorylated form which leads to neuron apoptosis and
CC transcriptional inactivation.
CC -!- SIMILARITY: Belongs to the MEF2 family. {ECO:0000305}.
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DR EMBL; S68893; AAB29973.1; -; mRNA.
DR EMBL; S68895; AAB29974.1; -; mRNA.
DR EMBL; AC137525; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS79939.1; -. [Q63943-1]
DR PIR; B56201; B56201.
DR RefSeq; NP_001297516.1; NM_001310587.1. [Q63943-1]
DR RefSeq; XP_006501152.1; XM_006501089.2. [Q63943-1]
DR RefSeq; XP_017174961.1; XM_017319472.1. [Q63943-1]
DR AlphaFoldDB; Q63943; -.
DR SMR; Q63943; -.
DR BioGRID; 201384; 8.
DR ELM; Q63943; -.
DR IntAct; Q63943; 5.
DR MINT; Q63943; -.
DR STRING; 10090.ENSMUSP00000001455; -.
DR iPTMnet; Q63943; -.
DR PhosphoSitePlus; Q63943; -.
DR EPD; Q63943; -.
DR jPOST; Q63943; -.
DR MaxQB; Q63943; -.
DR PaxDb; Q63943; -.
DR PRIDE; Q63943; -.
DR ProteomicsDB; 295994; -. [Q63943-1]
DR ProteomicsDB; 295995; -. [Q63943-2]
DR Antibodypedia; 1437; 495 antibodies from 35 providers.
DR DNASU; 17261; -.
DR Ensembl; ENSMUST00000107559; ENSMUSP00000103184; ENSMUSG00000001419. [Q63943-1]
DR GeneID; 17261; -.
DR KEGG; mmu:17261; -.
DR UCSC; uc008pua.1; mouse. [Q63943-1]
DR CTD; 4209; -.
DR MGI; MGI:99533; Mef2d.
DR VEuPathDB; HostDB:ENSMUSG00000001419; -.
DR eggNOG; KOG0014; Eukaryota.
DR GeneTree; ENSGT00940000159463; -.
DR InParanoid; Q63943; -.
DR OrthoDB; 729387at2759; -.
DR PhylomeDB; Q63943; -.
DR Reactome; R-MMU-525793; Myogenesis.
DR BioGRID-ORCS; 17261; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Mef2d; mouse.
DR PRO; PR:Q63943; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q63943; protein.
DR Bgee; ENSMUSG00000001419; Expressed in ileal epithelium and 271 other tissues.
DR ExpressionAtlas; Q63943; baseline and differential.
DR Genevisible; Q63943; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISO:MGI.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; IPI:BHF-UCL.
DR GO; GO:0042826; F:histone deacetylase binding; IDA:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:MGI.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0007512; P:adult heart development; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0002062; P:chondrocyte differentiation; IGI:MGI.
DR GO; GO:0001958; P:endochondral ossification; IGI:MGI.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:0001649; P:osteoblast differentiation; IGI:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0035914; P:skeletal muscle cell differentiation; IMP:MGI.
DR CDD; cd00265; MADS_MEF2_like; 1.
DR Gene3D; 3.40.1810.10; -; 1.
DR InterPro; IPR022102; HJURP_C.
DR InterPro; IPR033896; MADS_MEF2-like.
DR InterPro; IPR002100; TF_MADSbox.
DR InterPro; IPR036879; TF_MADSbox_sf.
DR Pfam; PF12347; HJURP_C; 1.
DR Pfam; PF00319; SRF-TF; 1.
DR PRINTS; PR00404; MADSDOMAIN.
DR SMART; SM00432; MADS; 1.
DR SUPFAM; SSF55455; SSF55455; 1.
DR PROSITE; PS00350; MADS_BOX_1; 1.
DR PROSITE; PS50066; MADS_BOX_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Alternative splicing; Apoptosis;
KW Developmental protein; Differentiation; DNA-binding; Isopeptide bond;
KW Neurogenesis; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..514
FT /note="Myocyte-specific enhancer factor 2D"
FT /id="PRO_0000199436"
FT DOMAIN 3..57
FT /note="MADS-box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00251"
FT DNA_BIND 58..86
FT /note="Mef2-type"
FT /evidence="ECO:0000255"
FT REGION 174..207
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 244..269
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 286..292
FT /note="Beta domain"
FT /evidence="ECO:0000250"
FT REGION 364..399
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 430..514
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 174..196
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 368..397
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 440..455
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 288..289
FT /note="Cleavage"
FT /evidence="ECO:0000305"
FT MOD_RES 98
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 106
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 110
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 121
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:18299387"
FT MOD_RES 180
FT /note="Phosphoserine; by MAPK7"
FT /evidence="ECO:0000250|UniProtKB:Q14814"
FT MOD_RES 190
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:18299387"
FT MOD_RES 231
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 245
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q14814"
FT MOD_RES 251
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19131326"
FT MOD_RES 432
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q14814"
FT MOD_RES 437
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:16407541"
FT CROSSLNK 432
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT VAR_SEQ 87..132
FT /note="TLRKKGFNGCDSPEPDGEDSLEQSPLLEDKYRRASEELDGLFRRYG -> AL
FT HNNDRECESPEVDEAFALTPQTEEKYKKIDEEKYKKIDEEFDKMMQSYRLA (in
FT isoform Muscle)"
FT /evidence="ECO:0000303|PubMed:8114702"
FT /id="VSP_006253"
FT VAR_SEQ 286..292
FT /note="Missing (in isoform Muscle)"
FT /evidence="ECO:0000303|PubMed:8114702"
FT /id="VSP_006254"
FT MUTAGEN 20
FT /note="T->A: No change in DNA-binding activity."
FT /evidence="ECO:0000269|PubMed:18299387"
FT MUTAGEN 20
FT /note="T->D: Dramatic decrease in DNA-binding."
FT /evidence="ECO:0000269|PubMed:18299387"
FT MUTAGEN 121
FT /note="S->A: Abolishes phosphorylation by PKA. No change in
FT protein levels. Loss of protein stability on PKA
FT stimulation. Loss of PKA-mediated repression. No change in
FT interaction with HDAC4 in response to PKA; when associated
FT with A-190."
FT /evidence="ECO:0000269|PubMed:18299387"
FT MUTAGEN 190
FT /note="S->A: Abolishes phosphorylation by PKA. No change in
FT protein levels. Loss of protein stability on PKA
FT stimulation mediated repression. No change in interaction
FT with HDAC4 in response to PKA; when associated with A-121."
FT /evidence="ECO:0000269|PubMed:18299387"
FT MUTAGEN 437
FT /note="S->A: Loss of calpain/Cdk5-mediated neuron
FT apoptosis."
FT /evidence="ECO:0000269|PubMed:16407541"
FT CONFLICT 287
FT /note="E -> G (in Ref. 1; AAB29973)"
FT /evidence="ECO:0000305"
FT MOD_RES Q63943-2:97
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES Q63943-2:107
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 514 AA; 55065 MW; 34833264CE22C63F CRC64;
MGRKKIQIQR ITDERNRQVT FTKRKFGLMK KAYELSVLCD CEIALIIFNH SNKLFQYAST
DMDKVLLKYT EYNEPHESRT NADIIETLRK KGFNGCDSPE PDGEDSLEQS PLLEDKYRRA
SEELDGLFRR YGSSVPAPNF AMPVTVPVSN QSSMQFSNPS SSLVTPSLVT SSLTDPRLLS
PQQPALQRNS VSPGLPQRPA SAGAMLGGDL NSANGACPSP VGNGYVSARA SPGLLPVANG
NSLNKVIPAK SPPPPTHNTQ LGAPSRKPDL RVITSQGGKG LMHHLTEDHL DLNNAQRLGV
SQSTHSLTTP VVSVATPSLL SQGLPFSSMP TAYNTDYQLP SAELSSLPAF SSPAGLALGN
VTAWQQPQPP QQPQPPQPPQ SQPQPPQPQP QQPPQQQPHL VPVSLSNLIP GSPLPHVGAA
LTVTTHPHIS IKSEPVSPSR ERSPAPPPPA VFPAARPEPG EGLSSPAGGS YETGDRDDGR
GDFGPTLGLL RPAPEPEAEG SAVKRMRLDT WTLK
