Reviewed, UniProtKB/Swiss-Prot Q06413 (MEF2C_HUMAN)

Names and origin

Protein names

Recommended name:
    Myocyte-specific enhancer factor 2C

Gene names

Name:

MEF2C

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	473 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. May also be involved in neurogenesis and in the development of cortical architecture By similarity. Isoform 3 and isoform 4, which lack the repressor domain, are more active than isoform 1 and isoform 2.
Subunit structure	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 EP300 in differentiating cells; the interaction acetylates MEF2C leading to increased DNA binding and activation. Interacts with HDAC7 and CARM1 By similarity. Interacts with HDAC4, HDAC7 AND HDAC9; the interaction WITH HDACs represses transcriptional activity.
Subcellular location	Nucleus.
Tissue specificity	Expressed in brain and skeletal muscle. Ref.5
Developmental stage	Expression is highest during the early stages of postnatal development, at later stages levels greatly decrease.
Domain	The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity By similarity.
Post-translational modification	Phosphorylation on Ser-59 enhances DNA binding activity By similarity. Phosphorylation on Ser-396 is required for Lys-391 sumoylation and inhibits transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation. Sumoylated on Lys-391 by SUMO2 but not by SUMO1 represses transcriptional activity. Ref.11 Ref.13 Ref.15 Proteolytically cleaved in cerebellar granule neurons, probably by caspase 7, following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation. Ref.3 Ref.4 Ref.7 Ref.10
Sequence similarities	Belongs to the MEF2 family. Contains 1 MADS-box domain. Contains 1 Mef2-type DNA-binding domain.

Ontologies

Keywords
Biological process	Apoptosis Differentiation Neurogenesis Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW muscle organ development Ref.2 Traceable author statement. Source: ProtInc negative regulation of specific transcription from RNA polymerase II promoter Inferred from mutant phenotype. Source: UniProtKB nervous system development Ref.2 Traceable author statement. Source: ProtInc positive regulation of survival gene product expression Inferred from mutant phenotype. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nuclear speck Inferred from direct assay. Source: UniProtKB
Molecular function	RNA polymerase II transcription factor activity Ref.2 Traceable author statement. Source: ProtInc sequence-specific DNA binding Inferred from electronic annotation. Source: InterPro transcription factor activity Non-traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: Q06413-1)

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.

Isoform 2 (identifier: Q06413-2)

Also known as: Muscle;

The sequence of this isoform differs from the canonical sequence as follows:
     271-278: Missing.

Isoform 3 (identifier: Q06413-3)

Also known as: hMEF2C-delta32; Brain;

The sequence of this isoform differs from the canonical sequence as follows:
     368-399: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 473	473	Myocyte-specific enhancer factor 2C		PRO_0000199433
Regions
	Domain	3 – 57	55	MADS-box
	DNA binding	58 – 86	29	Mef2-type Potential
	Region	271 – 278	8	Beta domain
	Region	368 – 399	32	Transcription repressor
	Compositional bias	4 – 31	28	Lys-rich (basic)
	Compositional bias	146 – 183	38	Ser-rich
Sites
	Site	432 – 433	2	Cleavage Probable
Amino acid modifications
	Modified residue	4	1	N6-acetyllysine
	Modified residue	59	1	Phosphoserine; by CK2 By similarity
	Modified residue	116	1	N6-acetyllysine Ref.14
	Modified residue	119	1	N6-acetyllysine Ref.14
	Modified residue	234	1	N6-acetyllysine Ref.14
	Modified residue	239	1	N6-acetyllysine Ref.14
	Modified residue	252	1	N6-acetyllysine Ref.14
	Modified residue	264	1	N6-acetyllysine Ref.14
	Modified residue	293	1	Phosphothreonine; by MAPK14 Ref.3 Ref.4
	Modified residue	300	1	Phosphothreonine; by MAPK14 Ref.3 Ref.4
	Modified residue	396	1	Phosphoserine; by CDK5 Ref.10
	Modified residue	419	1	Phosphoserine; by MAPK7 Ref.3 Ref.4
	Cross-link	391		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.13 Ref.15
Natural variations
	Alternative sequence	271 – 278	8	Missing in isoform 2.		VSP_006248
	Alternative sequence	368 – 399	32	Missing in isoform 3.		VSP_006249
Experimental info
	Mutagenesis	116	1	K → R: Reduced acetylation. Further reduction in acetylation; when associated with R-119. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-119; R-234; R-239; R-252; R-262.
	Mutagenesis	119	1	K → R: Reduced acetylation. Further reduction in acetylation; when associated with R-119. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-116; R-234; R-239; R-252; R-262.
	Mutagenesis	234	1	K → R: Reduced acetylation. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-116; R-119; R-239; R-252; R-264.
	Mutagenesis	239	1	K → R: Reduced acetylation. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-116; R-119; R-234; R-252; R-264.
	Mutagenesis	252	1	K → R: Reduced acetylation. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-116; R-119; R-234; R-239; R-264.
	Mutagenesis	264	1	K → R: Reduced acetylation. Complete loss of acetylation, 15% less transactivation activity and slightly reduced DNA binding; when associated with R-116; R-119; R-234; R-239; R-252.
	Mutagenesis	271	1	S → A: No effect on transcriptional activation. Ref.12
	Mutagenesis	272	1	E → Q: Reduced transcriptional activation. Completely abolishes transcriptional activation; when associated with Asn-273 and Asn-275. Ref.12
	Mutagenesis	273	1	D → N: Reduced transcriptional activation. Completely abolishes transcriptional activation; when associated with Gln-272 and Asn-275. Ref.12
	Mutagenesis	275	1	D → N: Reduced transcriptional activation. Completely abolishes transcriptional activation; when associated with Gln-272 and Asn-273. Ref.12
	Mutagenesis	293	1	T → A: Abolishes MAPK14-mediated phosphorylation. No effect on MAPK7-mediated phosphorylation.; when associated with A-300. Ref.3 Ref.4
	Mutagenesis	300	1	T → A: Abolishes MAPK14-mediated phosphorylation. No effect on MAPK7-mediated phosphorylation; when associated with A-293. Ref.3 Ref.4
	Mutagenesis	387	1	S → A: No change in transactivational avtivation for isoforms with or without the beta domain. Ref.12
	Mutagenesis	391	1	K → R: Abolishes sumoylation. Ref.15
	Mutagenesis	396	1	S → A or C: Abolishes sumoylation. Enhanced transcriptional activity. Ref.15 Ref.10 Ref.12
	Mutagenesis	396	1	S → A: No change in transactivational avtivation for isoforms with or without the beta domain. Ref.15 Ref.10 Ref.12
	Mutagenesis	396	1	S → E: No effect on sumoylation. No effect on transcriptional activity. Ref.15 Ref.10 Ref.12
	Mutagenesis	419	1	S → A: No effect on MAPK14-mediated phosphorylation. Abolishes MAPK7-mediated phosphorylation and reduces transactivation activity. Ref.3 Ref.4
	Mutagenesis	432	1	D → A: Abolishes cleavage by caspase 7. Ref.9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: A7982020BB8C8949	FASTA	473	51,221
	10 20 30 40 50 60 MGRKKIQITR IMDERNRQVT FTKRKFGLMK KAYELSVLCD CEIALIIFNS TNKLFQYAST 70 80 90 100 110 120 DMDKVLLKYT EYNEPHESRT NSDIVETLRK KGLNGCDSPD PDADDSVGHS PESEDKYRKI 130 140 150 160 170 180 NEDIDLMISR QRLCAVPPPN FEMPVSIPVS SHNSLVYSNP VSSLGNPNLL PLAHPSLQRN 190 200 210 220 230 240 SMSPGVTHRP PSAGNTGGLM GGDLTSGAGT SAGNGYGNPR NSPGLLVSPG NLNKNMQAKS 250 260 270 280 290 300 PPPMNLGMNN RKPDLRVLIP PGSKNTMPSV SEDVDLLLNQ RINNSQSAQS LATPVVSVAT 310 320 330 340 350 360 PTLPGQGMGG YPSAISTTYG TEYSLSSADL SSLSGFNTAS ALHLGSVTGW QQQHLHNMPP 370 380 390 400 410 420 SALSQLGACT STHLSQSSNL SLPSTQSLNI KSEPVSPPRD RTTTPSRYPQ HTRHEAGRSP 430 440 450 460 470 VDSLSSCSSS YDGSDREDHR NEFHSPIGLT RPSPDERESP SVKRMRLSEG WAT
	Isoform 2 (Muscle). Checksum: A2059C6AACB2F07B	FASTA	465	50,336
	10 20 30 40 50 60 MGRKKIQITR IMDERNRQVT FTKRKFGLMK KAYELSVLCD CEIALIIFNS TNKLFQYAST 70 80 90 100 110 120 DMDKVLLKYT EYNEPHESRT NSDIVETLRK KGLNGCDSPD PDADDSVGHS PESEDKYRKI 130 140 150 160 170 180 NEDIDLMISR QRLCAVPPPN FEMPVSIPVS SHNSLVYSNP VSSLGNPNLL PLAHPSLQRN 190 200 210 220 230 240 SMSPGVTHRP PSAGNTGGLM GGDLTSGAGT SAGNGYGNPR NSPGLLVSPG NLNKNMQAKS 250 260 270 280 290 300 PPPMNLGMNN RKPDLRVLIP PGSKNTMPSV NQRINNSQSA QSLATPVVSV ATPTLPGQGM 310 320 330 340 350 360 GGYPSAISTT YGTEYSLSSA DLSSLSGFNT ASALHLGSVT GWQQQHLHNM PPSALSQLGA 370 380 390 400 410 420 CTSTHLSQSS NLSLPSTQSL NIKSEPVSPP RDRTTTPSRY PQHTRHEAGR SPVDSLSSCS 430 440 450 460 SSYDGSDRED HRNEFHSPIG LTRPSPDERE SPSVKRMRLS EGWAT
	Isoform 3 (hMEF2C-delta32) (Brain). Checksum: BF94FD79A54FEEB1	FASTA	441	47,872
	10 20 30 40 50 60 MGRKKIQITR IMDERNRQVT FTKRKFGLMK KAYELSVLCD CEIALIIFNS TNKLFQYAST 70 80 90 100 110 120 DMDKVLLKYT EYNEPHESRT NSDIVETLRK KGLNGCDSPD PDADDSVGHS PESEDKYRKI 130 140 150 160 170 180 NEDIDLMISR QRLCAVPPPN FEMPVSIPVS SHNSLVYSNP VSSLGNPNLL PLAHPSLQRN 190 200 210 220 230 240 SMSPGVTHRP PSAGNTGGLM GGDLTSGAGT SAGNGYGNPR NSPGLLVSPG NLNKNMQAKS 250 260 270 280 290 300 PPPMNLGMNN RKPDLRVLIP PGSKNTMPSV SEDVDLLLNQ RINNSQSAQS LATPVVSVAT 310 320 330 340 350 360 PTLPGQGMGG YPSAISTTYG TEYSLSSADL SSLSGFNTAS ALHLGSVTGW QQQHLHNMPP 370 380 390 400 410 420 SALSQLGDRT TTPSRYPQHT RHEAGRSPVD SLSSCSSSYD GSDREDHRNE FHSPIGLTRP 430 440 SPDERESPSV KRMRLSEGWA T

References

[1]	"MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex." Leifer D., Krainc D., Yu Y.-T., McDermott J., Breitbart R.E., Heng J., Neve R.L., Kosofsky B., Nadal-Ginard B., Lipton S.A. Proc. Natl. Acad. Sci. U.S.A. 90:1546-1550(1993) [PubMed: 7679508] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3). Tissue: Fetal brain and Muscle.
[2]	"hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors." McDermott J.C., Cardoso M.C., Yu Y.-T., Andres V., Leifer D., Krainc D., Lipton S.A., Nadal-Ginard B. Mol. Cell. Biol. 13:2564-2577(1993) [PubMed: 8455629] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Skeletal muscle.
[3]	"BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C." Kato Y., Kravchenko V.V., Tapping R.I., Han J., Ulevitch R.J., Lee J.-D. EMBO J. 16:7054-7066(1997) [PubMed: 9384584] [Abstract] Cited for: PHOSPHORYLATION AT THR-293; THR-300 AND SER-419, FUNCTION, MUTAGENESIS OF THR-293; THR-300 AND SER-419.
[4]	"Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation." Han J., Jiang Y., Li Z., Kravchenko V.V., Ulevitch R.J. Nature 386:296-299(1997) [PubMed: 9069290] [Abstract] Cited for: PHOSPHORYLATION AT THR-293; THR-300 AND SER-419, FUNCTION, MUTAGENESIS OF THR-293; THR-300 AND SER-419.
[5]	"Characterization of myocyte enhancer factor 2 (MEF2) expression in B and T cells: MEF2C is a B cell-restricted transcription factor in lymphocytes." Swanson B.J., Jaeck H.-M., Lyons G.E. Mol. Immunol. 35:445-458(1998) [PubMed: 9798649] [Abstract] Cited for: TISSUE SPECIFICITY.
[6]	"HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor." Wang A.H., Bertos N.R., Vezmar M., Pelletier N., Crosato M., Heng H.H., Th'ng J., Han J., Yang X.-J. Mol. Cell. Biol. 19:7816-7827(1999) [PubMed: 10523670] [Abstract] Cited for: INTERACTION WITH HDAC4.
[7]	"Big mitogen-activated kinase regulates multiple members of the MEF2 protein family." Kato Y., Zhao M., Morikawa A., Sugiyama T., Chakravortty D., Koide N., Yoshida T., Tapping R.I., Yang Y., Yokochi T., Lee J.D. J. Biol. Chem. 275:18534-18540(2000) [PubMed: 10849446] [Abstract] Cited for: PHOSPHORYLATION BY MAPK7.
[8]	"Cloning and characterization of a histone deacetylase, HDAC9." Zhou X., Marks P.A., Rifkind R.A., Richon V.M. Proc. Natl. Acad. Sci. U.S.A. 98:10572-10577(2001) [PubMed: 11535832] [Abstract] Cited for: INTERACTION WITH HDAC9.
[9]	"Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis." Okamoto S., Li Z., Ju C., Scholzke M.N., Mathews E., Cui J., Salvesen G.S., Bossy-Wetzel E., Lipton S.A. Proc. Natl. Acad. Sci. U.S.A. 99:3974-3979(2002) [PubMed: 11904443] [Abstract] Cited for: PROTEOLYTIC PROCESSING AT ASP-432, FUNCTION, MUTAGENESIS OF ASP-432.
[10]	"Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity." Zhu B., Gulick T. Mol. Cell. Biol. 24:8264-8275(2004) [PubMed: 15340086] [Abstract] Cited for: PHOSPHORYLATION AT SER-396, MASS SPECTROMETRY, MUTAGENESIS OF SER-396, FUNCTION OF ISOFORMS.
[11]	"Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates." Gocke C.B., Yu H., Kang J. J. Biol. Chem. 280:5004-5012(2005) [PubMed: 15561718] [Abstract] Cited for: SUMOYLATION.
[12]	"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: 15834131] [Abstract] Cited for: FUNCTION OF BETA DOMAIN, MUTAGENESIS OF SER-271; GLU-272; ASP-273; ASP-275; SER-387 AND SER-396.
[13]	"Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors." Gregoire S., Yang X.-J. Mol. Cell. Biol. 25:2273-2287(2005) [PubMed: 15743823] [Abstract] Cited for: SUMOYLATION AT LYS-391.
[14]	"Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation." Ma K., Chan J.K., Zhu G., Wu Z. Mol. Cell. Biol. 25:3575-3582(2005) [PubMed: 15831463] [Abstract] Cited for: ACETYLATION AT LYS-116; LYS-119; LYS-234; LYS-239; LYS-252 AND LYS-264, INTERACTION WITH EP300, FUNCTION, DNA BINDING, MUTAGENSIS OF LYS-116; LYS-119; LYS-234; LYS-239; LYS-252 AND LYS-264.
[15]	"Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity." Kang J., Gocke C.B., Yu H. BMC Biochem. 7:5-5(2006) [PubMed: 16478538] [Abstract] Cited for: SUMOYLATION AT LYS-391, MUTAGENESIS OF LYS-391 AND SER-396.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	L08895 mRNA. Translation: AAA59578.1. S57212 mRNA. Translation: AAB25838.1.
IPI	IPI00215666. IPI00289092. IPI00334512.
PIR	A47284.
RefSeq	NP_002388.2.
UniGene	Hs.653394
3D structure databases
HSSP	HSSP built from PDB template 1EGW based on UniProtKB Q02078.
SMR	Q06413. Positions 2-93.
ModBase	Search...
PTM databases
PhosphoSite	Q06413.
Proteomic databases
PRIDE	Q06413.
Genome annotation databases
Ensembl	ENSG00000081189. Homo sapiens. [Contig view]
GeneID	4208.
Organism-specific databases
GeneCards	GC05M088051.
H-InvDB	HIX0005020.
HGNC	HGNC:6996. MEF2C.
HPA	HPA003214. HPA005533.
MIM	600662. gene.
PharmGKB	PA30734.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q06413.
HOVERGEN	Q06413.
Enzyme and pathway databases
Pathway_Interaction_DB	smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling. hdac_classii_pathway. Signaling events mediated by HDAC Class II. p38alphabetadownstreampathway. Signaling mediated by p38-alpha and p38-beta. mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.
Reactome	REACT_11061. Signalling by NGF.
Gene expression databases
ArrayExpress	Q06413.
Bgee	Q06413.
CleanEx	HS_MEF2C.
GermOnline	ENSG00000081189. Homo sapiens.
Family and domain databases
InterPro	IPR002100. TF_MADSbox. [Graphical view]
Pfam	PF00319. SRF-TF. 1 hit. [Graphical view]
PRINTS	PR00404. MADSDOMAIN.
SMART	SM00432. MADS. 1 hit. [Graphical view]
PROSITE	PS00350. MADS_BOX_1. 1 hit. PS50066. MADS_BOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	16578.
SOURCE	Search...

Entry information

Entry name

MEF2C_HUMAN

Accession

Primary (citable) accession number: Q06413

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1997
Last modified:	June 16, 2009
This is version 78 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)