MAFA_HUMAN
ID MAFA_HUMAN Reviewed; 353 AA.
AC Q8NHW3;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Transcription factor MafA;
DE AltName: Full=Pancreatic beta-cell-specific transcriptional activator;
DE AltName: Full=RIPE3b1 factor {ECO:0000303|PubMed:12011435};
DE AltName: Full=V-maf musculoaponeurotic fibrosarcoma oncogene homolog A;
GN Name=MAFA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12368292; DOI=10.1074/jbc.m206796200;
RA Kataoka K., Han S.I., Shioda S., Hirai M., Nishizawa M., Handa H.;
RT "MafA is a glucose-regulated and pancreatic beta-cell-specific
RT transcriptional activator for the insulin gene.";
RL J. Biol. Chem. 277:49903-49910(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, HOMODIMERIZATION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=12011435; DOI=10.1073/pnas.102168499;
RA Olbrot M., Rud J., Moss L.G., Sharma A.;
RT "Identification of beta-cell-specific insulin gene transcription factor
RT RIPE3b1 as mammalian MafA.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:6737-6742(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [4]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12917329; DOI=10.1128/mcb.23.17.6049-6062.2003;
RA Matsuoka T.A., Zhao L., Artner I., Jarrett H.W., Friedman D., Means A.,
RA Stein R.;
RT "Members of the large Maf transcription family regulate insulin gene
RT transcription in islet beta cells.";
RL Mol. Cell. Biol. 23:6049-6062(2003).
RN [5]
RP FUNCTION.
RX PubMed=15993959; DOI=10.1016/j.bbaexp.2005.05.009;
RA Aramata S., Han S.I., Yasuda K., Kataoka K.;
RT "Synergistic activation of the insulin gene promoter by the beta-cell
RT enriched transcription factors MafA, Beta2, and Pdx1.";
RL Biochim. Biophys. Acta 1730:41-46(2005).
RN [6]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-32, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.86 ANGSTROMS) OF 226-318 IN COMPLEX WITH DNA,
RP HOMODIMERIZATION, DNA-BINDING, AND FUNCTION.
RX PubMed=23148532; DOI=10.1021/bi301248j;
RA Lu X., Guanga G.P., Wan C., Rose R.B.;
RT "A novel DNA binding mechanism for maf basic region-leucine zipper factors
RT inferred from a MafA-DNA complex structure and binding specificities.";
RL Biochemistry 51:9706-9717(2012).
RN [8]
RP INVOLVEMENT IN INSDM, VARIANT INSDM PHE-64, AND CHARACTERIZATION OF VARIANT
RP INSDM PHE-64.
RX PubMed=29339498; DOI=10.1073/pnas.1712262115;
RA Iacovazzo D., Flanagan S.E., Walker E., Quezado R., de Sousa Barros F.A.,
RA Caswell R., Johnson M.B., Wakeling M., Braendle M., Guo M., Dang M.N.,
RA Gabrovska P., Niederle B., Christ E., Jenni S., Sipos B., Nieser M.,
RA Frilling A., Dhatariya K., Chanson P., de Herder W.W., Konukiewitz B.,
RA Kloeppel G., Stein R., Korbonits M., Ellard S.;
RT "missense mutation causes familial insulinomatosis and diabetes mellitus.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:1027-1032(2018).
CC -!- FUNCTION: Transcription factor that activates insulin gene expression
CC (PubMed:15993959, PubMed:12011435). Acts synergistically with
CC NEUROD1/BETA2 and PDX1 (PubMed:15993959). Binds the insulin enhancer
CC C1/RIPE3b element (PubMed:12011435). Binds to consensus TRE-type MARE
CC 5'-TGCTGACTCAGCA-3' DNA sequence (PubMed:23148532, PubMed:29339498).
CC {ECO:0000269|PubMed:12011435, ECO:0000269|PubMed:15993959,
CC ECO:0000269|PubMed:23148532, ECO:0000269|PubMed:29339498}.
CC -!- SUBUNIT: Forms homodimers or heterodimers (PubMed:12011435,
CC PubMed:23148532). Monomers and dimers are able to bind DNA, but the
CC off-rate is faster for monomers (PubMed:23148532). Interacts with
CC NEUROD1 and PDX1 (By similarity). May interact with MAFB, FOS, JUN and
CC PCAF (By similarity). {ECO:0000250|UniProtKB:O57342,
CC ECO:0000250|UniProtKB:Q8CF90, ECO:0000269|PubMed:12011435,
CC ECO:0000269|PubMed:23148532}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00978,
CC ECO:0000269|PubMed:12011435, ECO:0000269|PubMed:12917329}.
CC -!- TISSUE SPECIFICITY: Expressed in the islets of Langerhans (at protein
CC level). {ECO:0000269|PubMed:12917329}.
CC -!- PTM: Ubiquitinated, leading to its degradation by the proteasome.
CC {ECO:0000250|UniProtKB:O57342}.
CC -!- PTM: Phosphorylated at tyrosines. {ECO:0000250|UniProtKB:Q8CF90}.
CC -!- DISEASE: Insulinomatosis and diabetes mellitus (INSDM) [MIM:147630]: An
CC autosomal dominant disorder characterized by the occurrence of
CC multicentric insulinomas, hyperinsulinemic hypoglycemia, non insulin-
CC dependent diabetes mellitus, and impaired glucose tolerance. Some
CC patients also exhibit congenital cataract and/or congenital glaucoma.
CC {ECO:0000269|PubMed:29339498}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the bZIP family. Maf subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAFAID41235ch8q24.html";
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DR EMBL; AB086960; BAC20389.1; -; Genomic_DNA.
DR EMBL; AY083269; AAL89527.1; -; Genomic_DNA.
DR EMBL; AC105118; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS34955.1; -.
DR RefSeq; NP_963883.2; NM_201589.3.
DR PDB; 4EOT; X-ray; 2.86 A; A/B=226-318.
DR PDBsum; 4EOT; -.
DR AlphaFoldDB; Q8NHW3; -.
DR SMR; Q8NHW3; -.
DR BioGRID; 133233; 13.
DR IntAct; Q8NHW3; 2.
DR STRING; 9606.ENSP00000328364; -.
DR iPTMnet; Q8NHW3; -.
DR PhosphoSitePlus; Q8NHW3; -.
DR BioMuta; MAFA; -.
DR DMDM; 296435511; -.
DR MassIVE; Q8NHW3; -.
DR PaxDb; Q8NHW3; -.
DR PeptideAtlas; Q8NHW3; -.
DR PRIDE; Q8NHW3; -.
DR TopDownProteomics; Q8NHW3; -.
DR Antibodypedia; 14595; 257 antibodies from 26 providers.
DR DNASU; 389692; -.
DR Ensembl; ENST00000333480.3; ENSP00000328364.2; ENSG00000182759.4.
DR GeneID; 389692; -.
DR KEGG; hsa:389692; -.
DR MANE-Select; ENST00000333480.3; ENSP00000328364.2; NM_201589.4; NP_963883.2.
DR UCSC; uc003yyc.3; human.
DR CTD; 389692; -.
DR DisGeNET; 389692; -.
DR GeneCards; MAFA; -.
DR HGNC; HGNC:23145; MAFA.
DR HPA; ENSG00000182759; Tissue enriched (skeletal).
DR MalaCards; MAFA; -.
DR MIM; 147630; phenotype.
DR MIM; 610303; gene.
DR neXtProt; NX_Q8NHW3; -.
DR OpenTargets; ENSG00000182759; -.
DR PharmGKB; PA134963361; -.
DR VEuPathDB; HostDB:ENSG00000182759; -.
DR eggNOG; KOG4196; Eukaryota.
DR GeneTree; ENSGT00940000162747; -.
DR HOGENOM; CLU_063062_0_0_1; -.
DR InParanoid; Q8NHW3; -.
DR OMA; GAHHTAH; -.
DR OrthoDB; 1395389at2759; -.
DR PhylomeDB; Q8NHW3; -.
DR TreeFam; TF325689; -.
DR PathwayCommons; Q8NHW3; -.
DR Reactome; R-HSA-210745; Regulation of gene expression in beta cells.
DR SignaLink; Q8NHW3; -.
DR SIGNOR; Q8NHW3; -.
DR BioGRID-ORCS; 389692; 18 hits in 1089 CRISPR screens.
DR GeneWiki; MAFA_(gene); -.
DR GenomeRNAi; 389692; -.
DR Pharos; Q8NHW3; Tbio.
DR PRO; PR:Q8NHW3; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q8NHW3; protein.
DR Bgee; ENSG00000182759; Expressed in hindlimb stylopod muscle and 66 other tissues.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0030073; P:insulin secretion; IDA:BHF-UCL.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IDA:BHF-UCL.
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; TAS:UniProtKB.
DR GO; GO:0009749; P:response to glucose; IDA:UniProtKB.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR046347; bZIP_sf.
DR InterPro; IPR013592; Maf_TF_N.
DR InterPro; IPR028562; MafA.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR InterPro; IPR024874; Transcription_factor_Maf_fam.
DR PANTHER; PTHR10129; PTHR10129; 1.
DR PANTHER; PTHR10129:SF30; PTHR10129:SF30; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR Pfam; PF08383; Maf_N; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Diabetes mellitus; Disease variant; DNA-binding;
KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..353
FT /note="Transcription factor MafA"
FT /id="PRO_0000320274"
FT DOMAIN 254..317
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 40..108
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 177..219
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 254..279
FT /note="Basic motif"
FT REGION 282..303
FT /note="Leucine-zipper"
FT REGION 315..353
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 49..71
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 187..213
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT MOD_RES 49
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT MOD_RES 53
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT MOD_RES 57
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT MOD_RES 61
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT MOD_RES 65
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O57342"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 64
FT /note="S -> F (in INSDM; may prevent phosphorylation at S-
FT 65; may enhance protein stability; dbSNP:rs1554635488)"
FT /evidence="ECO:0000269|PubMed:29339498"
FT /id="VAR_080790"
FT CONFLICT 199
FT /note="Missing (in Ref. 1; BAC20389 and 2; AAL89527)"
FT /evidence="ECO:0000305"
FT HELIX 229..234
FT /evidence="ECO:0007829|PDB:4EOT"
FT HELIX 237..243
FT /evidence="ECO:0007829|PDB:4EOT"
FT TURN 244..246
FT /evidence="ECO:0007829|PDB:4EOT"
FT HELIX 249..316
FT /evidence="ECO:0007829|PDB:4EOT"
SQ SEQUENCE 353 AA; 36982 MW; 38F732D4C959AD62 CRC64;
MAAELAMGAE LPSSPLAIEY VNDFDLMKFE VKKEPPEAER FCHRLPPGSL SSTPLSTPCS
SVPSSPSFCA PSPGTGGGGG AGGGGGSSQA GGAPGPPSGG PGAVGGTSGK PALEDLYWMS
GYQHHLNPEA LNLTPEDAVE ALIGSGHHGA HHGAHHPAAA AAYEAFRGPG FAGGGGADDM
GAGHHHGAHH AAHHHHAAHH HHHHHHHHGG AGHGGGAGHH VRLEERFSDD QLVSMSVREL
NRQLRGFSKE EVIRLKQKRR TLKNRGYAQS CRFKRVQQRH ILESEKCQLQ SQVEQLKLEV
GRLAKERDLY KEKYEKLAGR GGPGSAGGAG FPREPSPPQA GPGGAKGTAD FFL
