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Protein

Mothers against decapentaplegic homolog 4

Gene

Smad4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein 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. 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)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi71 – 711ZincBy similarity
Metal bindingi115 – 1151ZincBy similarity
Metal bindingi127 – 1271ZincBy similarity
Metal bindingi132 – 1321ZincBy similarity
Sitei515 – 5151Necessary for heterotrimerizationBy similarity

GO - Molecular functioni

  • DNA binding Source: RGD
  • filamin binding Source: RGD
  • metal ion binding Source: UniProtKB-KW
  • SMAD binding Source: RGD
  • transcription factor activity, sequence-specific DNA binding Source: InterPro

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

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
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi3033. Smad4.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: In the cytoplasm in the absence of ligand. Migration to the nucleus when complexed with R-SMAD. PDPK1 prevents its nuclear translocation.By similarity

GO - Cellular componenti

  • cytoplasm Source: RGD
  • nucleus Source: RGD
  • protein complex Source: RGD
  • transcription factor complex Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 552552Mothers against decapentaplegic homolog 4PRO_0000090864Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei37 – 371N6-acetyllysineBy similarity
Cross-linki113 – 113Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei428 – 4281N6-acetyllysineBy similarity
Modified residuei507 – 5071N6-acetyllysineBy similarity
Cross-linki519 – 519Glycyl 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. Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling (By similarity).By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Ubl conjugation

PTM databases

iPTMnetiO70437.

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 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 (By similarity). Interacts with CITED1 and CITED2. Interacts with ZC3H3 (By similarity). 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 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • filamin binding Source: RGD
  • SMAD binding Source: RGD

Protein-protein interaction databases

IntActiO70437. 1 interaction.
MINTiMINT-2739642.

Structurei

3D structure databases

ProteinModelPortaliO70437.
SMRiO70437. Positions 19-138, 285-552.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini18 – 142125MH1PROSITE-ProRule annotationAdd
BLAST
Domaini323 – 552230MH2PROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni275 – 32046SADAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi451 – 46616Poly-AlaAdd
BLAST

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
Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

Phylogenomic databases

HOGENOMiHOG000286019.
HOVERGENiHBG053353.
InParanoidiO70437.
KOiK04501.
PhylomeDBiO70437.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
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. 3 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]

Sequencei

Sequence statusi: Complete.

O70437-1 [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
NAPPSMLVKD EYVHDFEGQP SLPTEGHSIQ TIQHPPSNRA STETYSAPAL
210 220 230 240 250
LAPSESNATS TTNFPNIPVA STSQPASILA GSHSEGLLQI ASGPQPGQQQ
260 270 280 290 300
NGFTAQPATY HHNSTTTWTG SRTAPYTPNL 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):60,469
Last modified:August 1, 1998 - v1
Checksum:i7AE0540AB4DF0E77
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB010954 mRNA. Translation: BAA83092.1.
AF056002 mRNA. Translation: AAC12781.1.
RefSeqiNP_062148.1. NM_019275.3.
UniGeneiRn.9774.

Genome annotation databases

GeneIDi50554.
KEGGirno:50554.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB010954 mRNA. Translation: BAA83092.1.
AF056002 mRNA. Translation: AAC12781.1.
RefSeqiNP_062148.1. NM_019275.3.
UniGeneiRn.9774.

3D structure databases

ProteinModelPortaliO70437.
SMRiO70437. Positions 19-138, 285-552.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiO70437. 1 interaction.
MINTiMINT-2739642.

PTM databases

iPTMnetiO70437.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi50554.
KEGGirno:50554.

Organism-specific databases

CTDi4089.
RGDi3033. Smad4.

Phylogenomic databases

HOGENOMiHOG000286019.
HOVERGENiHBG053353.
InParanoidiO70437.
KOiK04501.
PhylomeDBiO70437.

Miscellaneous databases

NextBioi610352.
PROiO70437.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
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. 3 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...

Publicationsi

  1. "Molecular cloning of rat Smad4 gene."
    Miyakita A., Okuno S., Watanabe T.K., Oga K., Tsuji A., Hishigaki H., Suto T., Nakagawa K., Nakahara Y., Higashi K.
    Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Skeletal muscle.
  2. "cDNA cloning and chromosomal mapping of rat Smad2 and Smad4 and their expression in cultured rat articular chondrocytes."
    Osaki M., Tsukazaki T., Ono N., Yonekura A., Hirota Y., Miyazaki Y., Shindo H., Sonta S., Yamashita S.
    Endocr. J. 46:695-701(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  3. "Cited2 modulates TGF-beta-mediated upregulation of MMP9."
    Chou Y.T., Wang H., Chen Y., Danielpour D., Yang Y.C.
    Oncogene 25:5547-5560(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CITED2.

Entry informationi

Entry nameiSMAD4_RAT
AccessioniPrimary (citable) accession number: O70437
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: August 1, 1998
Last modified: March 16, 2016
This is version 121 of the entry and version 1 of the sequence. [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

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.