The Human Transcription Factors

Conclusion

Assessment	Binding Mode	Motif Status	Notes	Comments
Known motif	1 Monomer or homomultimer	High-throughput in vitro

Description

Description:

SMAD family member 5 [Source:HGNC Symbol;Acc:HGNC:6771]

Entrez Summary

The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Ensembl ID:

ENSG00000113658

External Link:

CisBP

Interpro

IPR001132; IPR003619; IPR008984; IPR013019;

Protein Domain:

ENSP00000425749

Protein Domain:

ENSP00000426696

Protein Domain:

ENSP00000424279

Protein Domain:

ENSP00000427330

Protein Domain:

ENSP00000441954

Protein Domain:

ENSP00000427474

Domain:

Protein: ENSP00000425749	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000426696	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000424279	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000427330	DBD: MH1 Family DBDs	Other:
Protein: ENSP00000441954	DBD: MH1 Family DBDs	Other: IRF-3, MH2
Protein: ENSP00000427474	DBD: MH1 Family DBDs	Other: MH2

Previous Annotations

Source	Annotation
TF-CAT classification	TF Gene Candidate_DNA-Binding sequence-specific_DNA Binding_ PMIDS:11527422
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"	No
GO-Info	GO:0003700 sequence-specific DNA binding transcription factor activity IEA - GO_REF:0000002
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
HT-SELEX	Yin2017		Direct
Methyl-HT-SELEX	Yin2017		Direct
Transfac	Transfac	License required	Direct
Transfac	Transfac	License required	Direct
Transfac	Transfac	License required	Inferred - Smad5 (100% AA Identity, Mus musculus)
Transfac	Transfac	License required	Inferred - Smad5 (100% AA Identity, Rattus norvegicus)
Transfac	Transfac	License required	Inferred - SMAD1 (96% AA Identity, Homo sapiens)
Transfac	Transfac	License required	Inferred - SMAD1 (96% AA Identity, Homo sapiens)
Misc	HocoMoco		Inferred - SMAD1 (96% AA Identity, Homo sapiens)
Transfac	Transfac	License required	Inferred - SMAD9 (93% AA Identity, Homo sapiens)
Transfac	Transfac	License required	Inferred - Smad9 (93% AA Identity, Mus musculus)
Transfac	Transfac	License required	Inferred - Smad9 (93% AA Identity, Rattus norvegicus)
ChIP-chip	JASPAR		Inferred - Mad (87% AA Identity, Drosophila melanogaster)
Transfac	Transfac	License required	Inferred - Mad (87% AA Identity, Drosophila melanogaster)
Misc	iDMMPMM		Inferred - Mad (87% AA Identity, Drosophila melanogaster)

Structure

Structure	PDB	4ZKG

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": 128, "endStyle": "curved", "aliStart": 32, "text": "MH1", "colour": "#009900", "aliEnd": 128, "start": 31, "href": "http://pfam.xfam.org/family/PF03165.14", "type": "pfama", "display": "true", "metadata": {"end": 128, "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": 32, "scoreName": "E-value", "accession": "PF03165.14", "start": 31, "score": 1.6e-41, "identifier": "MH1 domain", "type": "DBD", "aliEnd": 128}}], "length": 128}

{"regions": [{"startStyle": "curved", "end": 132, "endStyle": "curved", "aliStart": 32, "text": "MH1", "colour": "#009900", "aliEnd": 132, "start": 31, "href": "http://pfam.xfam.org/family/PF03165.14", "type": "pfama", "display": "true", "metadata": {"end": 132, "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": 32, "scoreName": "E-value", "accession": "PF03165.14", "start": 31, "score": 2.5e-42, "identifier": "MH1 domain", "type": "DBD", "aliEnd": 132}}, {"startStyle": "straight", "end": 441, "endStyle": "straight", "aliStart": 269, "text": "MH2", "colour": "#9999ff", "aliEnd": 441, "start": 269, "href": "http://pfam.xfam.org/family/PF03166.12", "type": "pfama", "display": "true", "metadata": {"end": 441, "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": 269, "scoreName": "E-value", "accession": "PF03166.12", "start": 269, "score": 7.399999999999999e-76, "identifier": "MH2 domain", "type": "DBD", "aliEnd": 441}}, {"startStyle": "jagged", "end": 428, "endStyle": "jagged", "aliStart": 320, "text": "IRF-3", "colour": "#9999ff", "aliEnd": 403, "start": 310, "href": "http://pfam.xfam.org/family/PF10401.7", "type": "pfama", "display": "true", "metadata": {"end": 428, "description": "This is the interferon-regulatory factor 3 chain of the hetero-dimeric structure which also contains the shorter chain CREB-binding protein.  These two subunits make up the DRAF1 (double-stranded RNA-activated factor 1).          Viral dsRNA produced during viral transcription or replication leads to the activation of DRAF1. The DNA-binding specificity of DRAF1 correlates with transcriptional induction of ISG (interferon-alpha,beta-stimulated gene). IRF-3 preexists in the cytoplasm of uninfected cells and translocates to the nucleus following viral infection. Translocation of IRF-3 is accompanied by an increase in serine and threonine phosphorylation, and association with the CREB coactivator occurs only after infection.", "database": "PfamA", "aliStart": 320, "scoreName": "E-value", "accession": "PF10401.7", "start": 310, "score": 0.00041, "identifier": "Interferon-regulatory factor 3", "type": "DBD", "aliEnd": 403}}], "length": 466}

{"regions": [{"startStyle": "straight", "end": 161, "endStyle": "jagged", "aliStart": 92, "text": "MH2", "colour": "#9999ff", "aliEnd": 156, "start": 92, "href": "http://pfam.xfam.org/family/PF03166.12", "type": "pfama", "display": "true", "metadata": {"end": 161, "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": 92, "scoreName": "E-value", "accession": "PF03166.12", "start": 92, "score": 4.199999999999999e-25, "identifier": "MH2 domain", "type": "DBD", "aliEnd": 156}}], "length": 175}

TF Info Page for SMAD5 (SMAD)

Conclusion

Description

Previous Annotations

DNA-Binding

Published Motif Data

Structure

Experimental History

External Contribution