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Protein

Mothers against decapentaplegic homolog 4

Gene

SMAD4

Organism
Sus scrofa (Pig)
Status
Reviewed-Annotation score: -Experimental evidence at transcript leveli

Functioni

Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity). In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi71ZincBy similarity1
Metal bindingi115ZincBy similarity1
Metal bindingi127ZincBy similarity1
Metal bindingi132ZincBy similarity1
Sitei515Necessary for heterotrimerizationBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDNA-binding
Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-SSC-1181150 Signaling by NODAL
R-SSC-1502540 Signaling by Activin
R-SSC-201451 Signaling by BMP
R-SSC-2173789 TGF-beta receptor signaling activates SMADs
R-SSC-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-SSC-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-SSC-5689880 Ub-specific processing proteases
R-SSC-8941326 RUNX2 regulates bone development
R-SSC-8941855 RUNX3 regulates CDKN1A transcription

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 4
Short name:
MAD homolog 4
Short name:
Mothers against DPP homolog 4
Alternative name(s):
SMAD family member 4
Short name:
SMAD 4
Short name:
Smad4
Gene namesi
Name:SMAD4
Synonyms:MADH4
OrganismiSus scrofa (Pig)
Taxonomic identifieri9823 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaSuinaSuidaeSus
Proteomesi
  • UP000008227 Componenti: Chromosome 1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000908631 – 552Mothers against decapentaplegic homolog 4Add BLAST552

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei37N6-acetyllysineBy similarity1
Cross-linki113Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei428N6-acetyllysineBy similarity1
Modified residuei507N6-acetyllysineBy similarity1
Cross-linki519Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

Post-translational modificationi

Phosphorylated by PDPK1.By similarity
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling (By similarity).By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Ubl conjugation

Proteomic databases

PaxDbiQ9GKQ9
PeptideAtlasiQ9GKQ9
PRIDEiQ9GKQ9

Expressioni

Gene expression databases

BgeeiENSSSCG00000004524
GenevisibleiQ9GKQ9 SS

Interactioni

Subunit structurei

Monomer. Heterotrimer; with a C-terminally phosphorylated R-SMAD molecule and to form the transcriptionally active SMAD2/3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Found in a complex with SMAD1 and YY1. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts weakly with ZNF8. Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (By similarity). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (By similarity). Interacts with DLX1 (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi9823.ENSSSCP00000004879

Structurei

3D structure databases

ProteinModelPortaliQ9GKQ9
SMRiQ9GKQ9
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini18 – 142MH1PROSITE-ProRule annotationAdd BLAST125
Domaini323 – 552MH2PROSITE-ProRule annotationAdd BLAST230

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni275 – 320SADAdd BLAST46

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi451 – 466Poly-AlaAdd BLAST16

Domaini

The MH1 domain is required for DNA binding.By similarity
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import (By similarity).By similarity

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated

Phylogenomic databases

eggNOGiKOG3701 Eukaryota
ENOG410XQKU LUCA
GeneTreeiENSGT00760000119091
HOGENOMiHOG000286019
HOVERGENiHBG053353
InParanoidiQ9GKQ9
KOiK04501
OMAiPQMGPGT
OrthoDBiEOG091G05Z9
TreeFamiTF314923

Family and domain databases

Gene3Di2.60.200.10, 1 hit
3.90.520.10, 1 hit
InterProiView protein in InterPro
IPR013790 Dwarfin
IPR003619 MAD_homology1_Dwarfin-type
IPR013019 MAD_homology_MH1
IPR017855 SMAD-like_dom_sf
IPR001132 SMAD_dom_Dwarfin-type
IPR008984 SMAD_FHA_dom_sf
IPR036578 SMAD_MH1_sf
PANTHERiPTHR13703 PTHR13703, 1 hit
PfamiView protein in Pfam
PF03165 MH1, 1 hit
PF03166 MH2, 1 hit
SMARTiView protein in SMART
SM00523 DWA, 1 hit
SM00524 DWB, 1 hit
SUPFAMiSSF49879 SSF49879, 1 hit
SSF56366 SSF56366, 1 hit
PROSITEiView protein in PROSITE
PS51075 MH1, 1 hit
PS51076 MH2, 1 hit

Sequencei

Sequence statusi: Complete.

Q9GKQ9-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK
60 70 80 90 100
KDELDSLITA ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR
110 120 130 140 150
WPDLHKNELK HVKYCQYAFD LKCDSVCVNP YHYERVVSPG IDLSGLTLQS
160 170 180 190 200
NAPSGMLVKD EYVHDFEGQP SLATEGHSIQ TIQHPPSNRA STETYSTPAL
210 220 230 240 250
LAPSESNATS TTNFPNIPVA STSQPASILA GSHSEGLLQI ASGPQPGQQQ
260 270 280 290 300
NGFTGQPATY HHNSTTTWTG SRTAPYPPNL PHHQNGHLQH HPPMPPHPGH
310 320 330 340 350
YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV
360 370 380 390 400
DGYVDPSGGD RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR
410 420 430 440 450
CLSDHAVFVQ SYYLDREAGR APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ
460 470 480 490 500
AATAQAAAAA QAAAVAGNIP GPGSVGGIAP AISLSAAAGI GVDDLRRLCI
510 520 530 540 550
LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL HTMPIADPQP

LD
Length:552
Mass (Da):60,415
Last modified:March 1, 2001 - v1
Checksum:i4304796DE7571CB3
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB053483 mRNA Translation: BAB20909.1
RefSeqiNP_999237.1, NM_214072.1
XP_005654486.1, XM_005654429.2
XP_013840780.1, XM_013985326.1
UniGeneiSsc.249

Genome annotation databases

EnsembliENSSSCT00000004997; ENSSSCP00000004879; ENSSSCG00000004524
ENSSSCT00000045286; ENSSSCP00000058437; ENSSSCG00000004524
ENSSSCT00000058124; ENSSSCP00000050346; ENSSSCG00000004524
ENSSSCT00000059572; ENSSSCP00000041360; ENSSSCG00000004524
GeneIDi397142
KEGGissc:397142

Similar proteinsi

Entry informationi

Entry nameiSMAD4_PIG
AccessioniPrimary (citable) accession number: Q9GKQ9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: March 1, 2001
Last modified: June 20, 2018
This is version 134 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

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