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Protein

Mothers against decapentaplegic homolog 6

Gene

SMAD6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as a mediator of TGF-beta and BMP antiflammatory activity. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory elements in target promoter regions.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi205ZincBy similarity1
Metal bindingi247ZincBy similarity1
Metal bindingi260ZincBy similarity1
Metal bindingi265ZincBy similarity1

GO - Molecular functioni

  • chromatin binding Source: UniProtKB
  • co-SMAD binding Source: BHF-UCL
  • I-SMAD binding Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW
  • RNA polymerase II core promoter proximal region sequence-specific DNA binding Source: NTNU_SB
  • R-SMAD binding Source: BHF-UCL
  • transcription factor activity, sequence-specific DNA binding Source: InterPro
  • transcription regulatory region DNA binding Source: UniProtKB
  • transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity Source: BHF-UCL
  • type I activin receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

GO - Biological processi

  • aorta development Source: Ensembl
  • BMP signaling pathway Source: UniProtKB
  • cell-substrate adhesion Source: UniProtKB
  • coronary vasculature development Source: Ensembl
  • fat cell differentiation Source: UniProtKB
  • immune response Source: BHF-UCL
  • mitral valve morphogenesis Source: BHF-UCL
  • negative regulation of apoptotic process Source: BHF-UCL
  • negative regulation of BMP signaling pathway Source: BHF-UCL
  • negative regulation of cell proliferation Source: BHF-UCL
  • negative regulation of ossification Source: BHF-UCL
  • negative regulation of pathway-restricted SMAD protein phosphorylation Source: BHF-UCL
  • negative regulation of SMAD protein complex assembly Source: BHF-UCL
  • negative regulation of transforming growth factor beta receptor signaling pathway Source: BHF-UCL
  • outflow tract septum morphogenesis Source: BHF-UCL
  • positive regulation of pri-miRNA transcription from RNA polymerase II promoter Source: Ensembl
  • pulmonary valve morphogenesis Source: BHF-UCL
  • response to estrogen Source: Ensembl
  • response to laminar fluid shear stress Source: BHF-UCL
  • transcription, DNA-templated Source: UniProtKB-KW
  • transforming growth factor beta receptor signaling pathway Source: InterPro
  • ureteric bud development Source: Ensembl
  • ventricular septum development Source: Ensembl
  • zygotic specification of dorsal/ventral axis Source: BHF-UCL
Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000137834-MONOMER.
ReactomeiR-HSA-201451. Signaling by BMP.
SignaLinkiO43541.
SIGNORiO43541.

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 6
Short name:
MAD homolog 6
Short name:
Mothers against DPP homolog 6
Alternative name(s):
SMAD family member 6
Short name:
SMAD 6
Short name:
Smad6
Short name:
hSMAD6
Gene namesi
Name:SMAD6
Synonyms:MADH6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:6772. SMAD6.

Subcellular locationi

  • Nucleus 1 Publication

GO - Cellular componenti

  • cytoplasm Source: BHF-UCL
  • cytosol Source: Reactome
  • nucleus Source: UniProtKB
  • protein complex Source: MGI
  • transcription factor complex Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Aortic valve disease 2 (AOVD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry. SMAD6 variants may contribute to increased risk of congenital cardiovascular malformations (CVM). CVM is a major cause of mortality and morbidity in childhood. In most sporadic cases that cannot be attributed to particular malformation syndromes or teratogenic exposures, there remains a substantial excess familial risk, indicating a significant genetic contribution to disease susceptibility (PubMed:22275001).1 Publication
Disease descriptionA common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.
See also OMIM:614823
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068075415P → L in AOVD2; results in significantly lower activity than wild-type in inhibiting BMP signaling in a transcriptional reporter assay. 1 PublicationCorresponds to variant rs387907284dbSNPEnsembl.1
Natural variantiVAR_068076484C → F in AOVD2; results in significantly lower activity than wild-type in inhibiting BMP signaling in a transcriptional reporter assay. 1 PublicationCorresponds to variant rs387907283dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi173K → R: Abolishes monoubiquitination by UBE2O. 1 Publication1
Mutagenesisi435S → A: Loss of in vitro phosphorylation by PRKX. 1 Publication1
Mutagenesisi471G → S: Loss of SMAD1-binding and of inhibition of BMP-SMAD1 signaling. No effect on interaction with BMPR1B and TGFBR1. 1 Publication1
Mutagenesisi478 – 496Missing : Loss of interaction with BMPR1B, TGFBR1 and SMAD1. 1 PublicationAdd BLAST19

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4091.
MalaCardsiSMAD6.
MIMi614823. phenotype.
OpenTargetsiENSG00000137834.
Orphaneti402075. Familial bicuspid aortic valve.
PharmGKBiPA30529.

Polymorphism and mutation databases

BioMutaiSMAD6.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000908691 – 496Mothers against decapentaplegic homolog 6Add BLAST496

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei75Dimethylated arginine; alternateBy similarity1
Modified residuei75Omega-N-methylarginine; alternateBy similarity1
Modified residuei82Dimethylated arginine; alternateBy similarity1
Modified residuei82Omega-N-methylarginine; alternateBy similarity1
Cross-linki173Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei435Phosphoserine; by PRKX; in vitroPROSITE-ProRule annotation1 Publication1

Post-translational modificationi

Phosphorylated by BMP type 1 receptor kinase and by PRKX.1 Publication
Ubiquitinated by WWP1 (By similarity). Monoubiquitinated at Lys-173 by the E2/E3 hybrid ubiquitin-protein ligase UBE2O, leading to reduced binding affinity for the activated BMP type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating adipocyte differentiation.By similarity1 Publication
Arginine methylation by PRMT1, which is recruited by BMPR2, initiates BMP-Induced signaling and induces dissociation from the BMPR1B receptor at the cell surface leading to derepress downstream Smad1/Smad5 signaling.By similarity

Keywords - PTMi

Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO43541.
PaxDbiO43541.
PeptideAtlasiO43541.
PRIDEiO43541.

PTM databases

iPTMnetiO43541.
PhosphoSitePlusiO43541.

Expressioni

Tissue specificityi

Ubiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.

Gene expression databases

BgeeiENSG00000137834.
CleanExiHS_SMAD6.
ExpressionAtlasiO43541. baseline and differential.
GenevisibleiO43541. HS.

Organism-specific databases

HPAiHPA061917.

Interactioni

Subunit structurei

Interacts with NEDD4L (By similarity). Interacts with WWP1 (By similarity). Interacts with STAMBP and PRKX. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in response to IL1B and hence negatively regulates IL1R-TLR signaling.By similarity7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-976374,EBI-976374
PRKXP518175EBI-976374,EBI-4302903
RUNX2Q139503EBI-976374,EBI-976402
SMAD1Q157974EBI-976374,EBI-1567153
STAMBPO956302EBI-4324970,EBI-396676

GO - Molecular functioni

  • co-SMAD binding Source: BHF-UCL
  • I-SMAD binding Source: BHF-UCL
  • R-SMAD binding Source: BHF-UCL
  • type I activin receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110266. 47 interactors.
DIPiDIP-36708N.
IntActiO43541. 11 interactors.
MINTiMINT-1198639.
STRINGi9606.ENSP00000288840.

Structurei

3D structure databases

ProteinModelPortaliO43541.
SMRiO43541.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini148 – 275MH1PROSITE-ProRule annotationAdd BLAST128
Domaini331 – 496MH2PROSITE-ProRule annotationAdd BLAST166

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi25 – 33Poly-Gly9
Compositional biasi82 – 85Poly-Arg4
Compositional biasi165 – 168Poly-Leu4
Compositional biasi251 – 254Poly-Ala4
Compositional biasi275 – 278Poly-Pro4

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated
Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOVERGENiHBG053021.
InParanoidiO43541.
KOiK04677.
OMAiCRTVTCC.
OrthoDBiEOG091G0XBN.
PhylomeDBiO43541.
TreeFamiTF314923.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 2 hits.
InterProiIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
PANTHERiPTHR13703. PTHR13703. 2 hits.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform A (identifier: O43541-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MFRSKRSGLV RRLWRSRVVP DREEGGSGGG GGGDEDGSLG SRAEPAPRAR
60 70 80 90 100
EGGGCGRSEV RPVAPRRPRD AVGQRGAQGA GRRRRAGGPP RPMSEPGAGA
110 120 130 140 150
GSSLLDVAEP GGPGWLPESD CETVTCCLFS ERDAAGAPRD ASDPLAGAAL
160 170 180 190 200
EPAGGGRSRE ARSRLLLLEQ ELKTVTYSLL KRLKERSLDT LLEAVESRGG
210 220 230 240 250
VPGGCVLVPR ADLRLGGQPA PPQLLLGRLF RWPDLQHAVE LKPLCGCHSF
260 270 280 290 300
AAAADGPTVC CNPYHFSRLC GPESPPPPYS RLSPRDEYKP LDLSDSTLSY
310 320 330 340 350
TETEATNSLI TAPGEFSDAS MSPDATKPSH WCSVAYWEHR TRVGRLYAVY
360 370 380 390 400
DQAVSIFYDL PQGSGFCLGQ LNLEQRSESV RRTRSKIGFG ILLSKEPDGV
410 420 430 440 450
WAYNRGEHPI FVNSPTLDAP GGRALVVRKV PPGYSIKVFD FERSGLQHAP
460 470 480 490
EPDAADGPYD PNSVRISFAK GWGPCYSRQF ITSCPCWLEI LLNNPR
Length:496
Mass (Da):53,497
Last modified:October 3, 2006 - v2
Checksum:iA4B928AE2D34EBC2
GO
Isoform B (identifier: O43541-2) [UniParc]FASTAAdd to basket
Also known as: Smad 6S

The sequence of this isoform differs from the canonical sequence as follows:
     1-261: Missing.
     262-273: NPYHFSRLCGPE → MSRMGKPIETQK

Show »
Length:235
Mass (Da):26,236
Checksum:i0847C2C84DC0B2A2
GO
Isoform D (identifier: O43541-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     318-338: DASMSPDATKPSHWCSVAYWE → AADAGIGSRGNRGLESSVPCS
     339-496: Missing.

Show »
Length:338
Mass (Da):35,467
Checksum:iC4D02353D7FD76CE
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti21D → N in AAB94137 (PubMed:9436979).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068074325A → T Found in a patient with congenital mitral valve prolapse. 1 PublicationCorresponds to variant rs199822239dbSNPEnsembl.1
Natural variantiVAR_068075415P → L in AOVD2; results in significantly lower activity than wild-type in inhibiting BMP signaling in a transcriptional reporter assay. 1 PublicationCorresponds to variant rs387907284dbSNPEnsembl.1
Natural variantiVAR_068076484C → F in AOVD2; results in significantly lower activity than wild-type in inhibiting BMP signaling in a transcriptional reporter assay. 1 PublicationCorresponds to variant rs387907283dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0061791 – 261Missing in isoform B. 1 PublicationAdd BLAST261
Alternative sequenceiVSP_006180262 – 273NPYHF…LCGPE → MSRMGKPIETQK in isoform B. 1 PublicationAdd BLAST12
Alternative sequenceiVSP_035489318 – 338DASMS…VAYWE → AADAGIGSRGNRGLESSVPC S in isoform D. 1 PublicationAdd BLAST21
Alternative sequenceiVSP_035490339 – 496Missing in isoform D. 1 PublicationAdd BLAST158

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59914 mRNA. Translation: AAC50792.1.
AF035528 mRNA. Translation: AAB94137.1.
AF043640 mRNA. Translation: AAC00497.1.
AF037469 mRNA. Translation: AAC82331.1.
AF041065
, AF041062, AF041063, AF041064 Genomic DNA. Translation: AAF14343.1.
AM909653 mRNA. Translation: CAP20377.1.
BC012986 mRNA. Translation: AAH12986.1.
AF101474 Genomic DNA. Translation: AAF06841.1.
CCDSiCCDS10221.1. [O43541-1]
RefSeqiNP_005576.3. NM_005585.4. [O43541-1]
XP_011519863.1. XM_011521561.2. [O43541-2]
UniGeneiHs.153863.

Genome annotation databases

EnsembliENST00000288840; ENSP00000288840; ENSG00000137834. [O43541-1]
ENST00000557916; ENSP00000452955; ENSG00000137834. [O43541-4]
GeneIDi4091.
KEGGihsa:4091.
UCSCiuc002aqf.4. human. [O43541-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59914 mRNA. Translation: AAC50792.1.
AF035528 mRNA. Translation: AAB94137.1.
AF043640 mRNA. Translation: AAC00497.1.
AF037469 mRNA. Translation: AAC82331.1.
AF041065
, AF041062, AF041063, AF041064 Genomic DNA. Translation: AAF14343.1.
AM909653 mRNA. Translation: CAP20377.1.
BC012986 mRNA. Translation: AAH12986.1.
AF101474 Genomic DNA. Translation: AAF06841.1.
CCDSiCCDS10221.1. [O43541-1]
RefSeqiNP_005576.3. NM_005585.4. [O43541-1]
XP_011519863.1. XM_011521561.2. [O43541-2]
UniGeneiHs.153863.

3D structure databases

ProteinModelPortaliO43541.
SMRiO43541.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110266. 47 interactors.
DIPiDIP-36708N.
IntActiO43541. 11 interactors.
MINTiMINT-1198639.
STRINGi9606.ENSP00000288840.

PTM databases

iPTMnetiO43541.
PhosphoSitePlusiO43541.

Polymorphism and mutation databases

BioMutaiSMAD6.

Proteomic databases

MaxQBiO43541.
PaxDbiO43541.
PeptideAtlasiO43541.
PRIDEiO43541.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000288840; ENSP00000288840; ENSG00000137834. [O43541-1]
ENST00000557916; ENSP00000452955; ENSG00000137834. [O43541-4]
GeneIDi4091.
KEGGihsa:4091.
UCSCiuc002aqf.4. human. [O43541-1]

Organism-specific databases

CTDi4091.
DisGeNETi4091.
GeneCardsiSMAD6.
H-InvDBHIX0132566.
HGNCiHGNC:6772. SMAD6.
HPAiHPA061917.
MalaCardsiSMAD6.
MIMi602931. gene.
614823. phenotype.
neXtProtiNX_O43541.
OpenTargetsiENSG00000137834.
Orphaneti402075. Familial bicuspid aortic valve.
PharmGKBiPA30529.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOVERGENiHBG053021.
InParanoidiO43541.
KOiK04677.
OMAiCRTVTCC.
OrthoDBiEOG091G0XBN.
PhylomeDBiO43541.
TreeFamiTF314923.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000137834-MONOMER.
ReactomeiR-HSA-201451. Signaling by BMP.
SignaLinkiO43541.
SIGNORiO43541.

Miscellaneous databases

ChiTaRSiSMAD6. human.
GeneWikiiMothers_against_decapentaplegic_homolog_6.
GenomeRNAii4091.
PROiO43541.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000137834.
CleanExiHS_SMAD6.
ExpressionAtlasiO43541. baseline and differential.
GenevisibleiO43541. HS.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 2 hits.
InterProiIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
PANTHERiPTHR13703. PTHR13703. 2 hits.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSMAD6_HUMAN
AccessioniPrimary (citable) accession number: O43541
Secondary accession number(s): A9J6M5
, O43654, Q15799, Q7Z7L4, Q96E31, Q9UKZ3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: October 3, 2006
Last modified: November 2, 2016
This is version 161 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.