The Human Transcription Factors

Conclusion

Assessment	Binding Mode	Motif Status	Notes	Comments
Known motif	1 Monomer or homomultimer	100 perc ID - in vitro

Description

Description:	SMAD family member 4 [Source:HGNC Symbol;Acc:HGNC:6770]
Entrez Summary	TBA
Ensembl ID:	ENSG00000141646
External Link:	T141883_1.02
Interpro	IPR001132; IPR003619; IPR008984; IPR013019;
Protein Domain:
Protein: ENSP00000465874	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000466941	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000466118	DBD: MH1 Family DBDs	Other: MH2

Previous Annotations

Source	Annotation
TF-CAT classification	No PMIDS:
Vaquerizas 2009 TF classification "a" Has direct evidence of TF function; "b" Has evidence for an orthologous TF; "c" contains likely DBDs, but has no functional evidence; "x" is an unlikely TF such as predicted gene, genes with likely non-specific DBDs or that have function outside transcription; "other" category contains proteins without clear DBDs they curated from external sources.	a
CisBP considers it as a TF?	Yes
TFclass considers it as a TF?	Yes
Has GO:0003700 "transcription factor activity, sequence-specific DNA binding"	Yes
GO-Info	GO:0001077 RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor a IDA - PMID:9389648 GO:0003700 sequence-specific DNA binding transcription factor activity IDA - PMID:10823886, PMID:17438144
Initial Assessment 1a1 Protein has a high confidence PWM (HT-SELEX, PBM or B1H model) or there is a crystal structure that supports sequence specific DNA binding; 1a2 There is high confidence data for a close ortholog (as defined in CisBP); 2a1 There is lower confidence direct evidence, such as a Jaspar, Hocomoco or Transfac model; 2a2 There is lower confidence evidence for an close ortholog; 3a There is decent circumstantial evidence for its role as a TF or not; 4a Two or more datasets predict it as a TF; 5a One of the source datasets predicts is as a TF	1a1, Direct HQ evidence
TF has conditional DNA-binding requirements

DNA-Binding

Published Motif Data

Source	Annotation	Motif	Evidence
Transfac	Transfac	License required	Direct
Transfac	Transfac	License required	Direct
Transfac	Transfac	License required	Direct
Misc	HocoMoco		Direct
Misc	HOMER		Direct
SMiLE-seq	Isakova2017		Inferred - SMAD4 (100% AA Identity, Mus musculus)
Misc	iDMMPMM		Inferred - Med (96% AA Identity, Drosophila melanogaster)

Structure

Structure	PDB	3QSV

Experimental History

Method	Constructs
Tried in PBM? (Whether the protein was tried in PBM or not)
Tried in HT-SELEX (Whether the protein was tried in HT-SELEX or not, and if so, then what kind of clones were tested)
Other Information? (Tried with another method and failed?)

External Contribution

Name
Email
Comment
Reference

{"regions": [{"startStyle": "curved", "end": 120, "endStyle": "jagged", "aliStart": 37, "text": "MH1", "colour": "#009900", "aliEnd": 119, "start": 36, "href": "http://pfam.xfam.org/family/PF03165.14", "type": "pfama", "display": "true", "metadata": {"end": 120, "description": "The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related proteins such as Smads. This domain is separated from the MH2 domain by a non-conserved linker region. The crystal structure of the MH1 domain shows that a highly conserved 11 residue beta hairpin is used to bind the DNA consensus sequence GNCN in the major groove, shown to be vital for the transcriptional activation of target genes. Not all examples of MH1 can bind to DNA however.  Smad2 cannot bind DNA and has a large insertion within the hairpin that presumably abolishes DNA binding. A basic helix (H2) in MH1 with the nuclear localisation signal KKLKK has been shown to be essential for Smad3 nuclear import. Smads also use the MH1 domain to interact with transcription factors such as Jun, TFE3, Sp1, and Runx [1,3].", "database": "PfamA", "aliStart": 37, "scoreName": "E-value", "accession": "PF03165.14", "start": 36, "score": 8.1e-31, "identifier": "MH1 domain", "type": "DBD", "aliEnd": 119}}], "length": 120}

{"regions": [{"startStyle": "curved", "end": 137, "endStyle": "curved", "aliStart": 37, "text": "MH1", "colour": "#009900", "aliEnd": 137, "start": 36, "href": "http://pfam.xfam.org/family/PF03165.14", "type": "pfama", "display": "true", "metadata": {"end": 137, "description": "The MH1 (MAD homology 1) domain is found at the amino terminus of MAD related proteins such as Smads. This domain is separated from the MH2 domain by a non-conserved linker region. The crystal structure of the MH1 domain shows that a highly conserved 11 residue beta hairpin is used to bind the DNA consensus sequence GNCN in the major groove, shown to be vital for the transcriptional activation of target genes. Not all examples of MH1 can bind to DNA however.  Smad2 cannot bind DNA and has a large insertion within the hairpin that presumably abolishes DNA binding. A basic helix (H2) in MH1 with the nuclear localisation signal KKLKK has been shown to be essential for Smad3 nuclear import. Smads also use the MH1 domain to interact with transcription factors such as Jun, TFE3, Sp1, and Runx [1,3].", "database": "PfamA", "aliStart": 37, "scoreName": "E-value", "accession": "PF03165.14", "start": 36, "score": 4.9e-41, "identifier": "MH1 domain", "type": "DBD", "aliEnd": 137}}], "length": 151}

{"regions": [{"startStyle": "jagged", "end": 81, "endStyle": "jagged", "aliStart": 1, "text": "MH2", "colour": "#9999ff", "aliEnd": 48, "start": 1, "href": "http://pfam.xfam.org/family/PF03166.12", "type": "pfama", "display": "true", "metadata": {"end": 81, "description": "This is the MH2 (MAD homology 2) domain found at the carboxy terminus of MAD related proteins such as Smads. This domain is separated from the MH1 domain by a non-conserved linker region. The MH2 domain mediates interaction with a wide variety of proteins and provides specificity and selectivity to Smad function and also is critical for mediating interactions in Smad oligomers. Unlike MH1, MH2 does not bind DNA. The well-studied MH2 domain of Smad4 is composed of five alpha helices and three loops enclosing a beta sandwich. Smads are involved in the propagation of TGF-beta signals by direct association with the TGF-beta receptor kinase which phosphorylates the last two Ser of a conserved 'SSXS' motif located at the C-terminus of MH2 [1-3].", "database": "PfamA", "aliStart": 1, "scoreName": "E-value", "accession": "PF03166.12", "start": 1, "score": 2e-09, "identifier": "MH2 domain", "type": "DBD", "aliEnd": 48}}], "length": 83}

TF Info Page for SMAD4 (SMAD)