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Q13485

- SMAD4_HUMAN

UniProt

Q13485 - SMAD4_HUMAN

Protein

Mothers against decapentaplegic homolog 4

Gene

SMAD4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 168 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    Functioni

    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. 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 By similarity. 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 syngernistic transcriptional activity in response to TGF-beta. 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 similarity2 Publications

    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 heterotrimerization

    GO - Molecular functioni

    1. chromatin binding Source: Ensembl
    2. core promoter proximal region sequence-specific DNA binding Source: UniProtKB
    3. identical protein binding Source: BHF-UCL
    4. I-SMAD binding Source: BHF-UCL
    5. metal ion binding Source: UniProtKB-KW
    6. protein binding Source: UniProtKB
    7. protein homodimerization activity Source: BHF-UCL
    8. RNA polymerase II transcription factor binding transcription factor activity Source: Ensembl
    9. R-SMAD binding Source: BHF-UCL
    10. sequence-specific DNA binding transcription factor activity Source: Ensembl
    11. transcription regulatory region DNA binding Source: BHF-UCL
    12. transforming growth factor beta receptor, common-partner cytoplasmic mediator activity Source: BHF-UCL

    GO - Biological processi

    1. atrioventricular canal development Source: Ensembl
    2. atrioventricular valve formation Source: Ensembl
    3. axon guidance Source: Ensembl
    4. BMP signaling pathway Source: BHF-UCL
    5. brainstem development Source: Ensembl
    6. branching involved in ureteric bud morphogenesis Source: Ensembl
    7. cardiac septum development Source: Ensembl
    8. cell proliferation Source: Ensembl
    9. developmental growth Source: Ensembl
    10. endocardial cell differentiation Source: Ensembl
    11. endoderm development Source: Ensembl
    12. endothelial cell activation Source: Ensembl
    13. epithelial to mesenchymal transition involved in endocardial cushion formation Source: Ensembl
    14. formation of anatomical boundary Source: Ensembl
    15. gastrulation with mouth forming second Source: Ensembl
    16. gene expression Source: Reactome
    17. intracellular signal transduction Source: GOC
    18. in utero embryonic development Source: Ensembl
    19. mesoderm development Source: Ensembl
    20. metanephric mesenchyme morphogenesis Source: Ensembl
    21. negative regulation of cell death Source: Ensembl
    22. negative regulation of cell growth Source: BHF-UCL
    23. negative regulation of cell proliferation Source: Ensembl
    24. negative regulation of protein catabolic process Source: BHF-UCL
    25. negative regulation of transcription, DNA-templated Source: BHF-UCL
    26. negative regulation of transcription from RNA polymerase II promoter Source: Reactome
    27. nephrogenic mesenchyme morphogenesis Source: Ensembl
    28. neural crest cell differentiation Source: Ensembl
    29. neuron fate commitment Source: Ensembl
    30. palate development Source: BHF-UCL
    31. positive regulation of BMP signaling pathway Source: BHF-UCL
    32. positive regulation of cell proliferation involved in heart valve morphogenesis Source: Ensembl
    33. positive regulation of epithelial to mesenchymal transition Source: BHF-UCL
    34. positive regulation of pathway-restricted SMAD protein phosphorylation Source: BHF-UCL
    35. positive regulation of SMAD protein import into nucleus Source: BHF-UCL
    36. positive regulation of transcription, DNA-templated Source: UniProtKB
    37. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    38. positive regulation of transforming growth factor beta receptor signaling pathway Source: BHF-UCL
    39. regulation of binding Source: Ensembl
    40. regulation of hair follicle development Source: Ensembl
    41. regulation of transforming growth factor beta2 production Source: BHF-UCL
    42. regulation of transforming growth factor beta receptor signaling pathway Source: BHF-UCL
    43. response to hypoxia Source: BHF-UCL
    44. response to transforming growth factor beta Source: UniProtKB
    45. sebaceous gland development Source: Ensembl
    46. SMAD protein complex assembly Source: BHF-UCL
    47. SMAD protein signal transduction Source: BHF-UCL
    48. somite rostral/caudal axis specification Source: Ensembl
    49. transcription, DNA-templated Source: Reactome
    50. transcription initiation from RNA polymerase II promoter Source: Reactome
    51. transforming growth factor beta receptor signaling pathway Source: BHF-UCL

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_111057. Signaling by NODAL.
    REACT_12034. Signaling by BMP.
    REACT_120734. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_120850. TGF-beta receptor signaling activates SMADs.
    REACT_121111. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_150238. Signaling by Activin.
    REACT_169107. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_169165. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_200812. Transcriptional regulation of pluripotent stem cells.
    SignaLinkiQ13485.

    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):
    Deletion target in pancreatic carcinoma 4
    SMAD family member 4
    Short name:
    SMAD 4
    Short name:
    Smad4
    Short name:
    hSMAD4
    Gene namesi
    Name:SMAD4
    Synonyms:DPC4, MADH4
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 18

    Organism-specific databases

    HGNCiHGNC:6770. SMAD4.

    Subcellular locationi

    Cytoplasm. Nucleus
    Note: Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD. PDPK1 prevents its nuclear translocation in response to TGF-beta.

    GO - Cellular componenti

    1. activin responsive factor complex Source: BHF-UCL
    2. centrosome Source: HPA
    3. cytoplasm Source: BHF-UCL
    4. cytosol Source: Reactome
    5. nuclear chromatin Source: BHF-UCL
    6. nucleoplasm Source: Reactome
    7. nucleus Source: BHF-UCL
    8. SMAD protein complex Source: UniProtKB
    9. transcription factor complex Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
    Note: The gene represented in this entry may be involved in disease pathogenesis.
    Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti330 – 3301E → G in JPS. 1 Publication
    Corresponds to variant rs281875324 [ dbSNP | Ensembl ].
    VAR_022833
    Natural varianti352 – 3521G → R in JP/HHT and JPS. 2 Publications
    Corresponds to variant rs121912581 [ dbSNP | Ensembl ].
    VAR_019571
    Natural varianti361 – 3611R → C in JPS. 1 Publication
    Corresponds to variant rs80338963 [ dbSNP | Ensembl ].
    VAR_019572
    Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti352 – 3521G → R in JP/HHT and JPS. 2 Publications
    Corresponds to variant rs121912581 [ dbSNP | Ensembl ].
    VAR_019571
    Natural varianti386 – 3861G → D in JP/HHT. 1 Publication
    Corresponds to variant rs28936393 [ dbSNP | Ensembl ].
    VAR_019573
    Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
    Note: The disease may be caused by mutations affecting the gene represented in this entry.
    SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.
    Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti500 – 5001I → M in MYHRS. 1 Publication
    Corresponds to variant rs281875320 [ dbSNP | Ensembl ].
    VAR_067602
    Natural varianti500 – 5001I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. 2 Publications
    Corresponds to variant rs281875321 [ dbSNP | Ensembl ].
    VAR_067603
    Natural varianti500 – 5001I → V in MYHRS. 2 Publications
    Corresponds to variant rs281875322 [ dbSNP | Ensembl ].
    VAR_067604

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi416 – 4161R → S: No effect on heterotrimerization. Partially diminished transcriptional activation. 1 Publication
    Mutagenesisi496 – 4961R → S: No effect on heterotrimerization. Partially diminished transcriptional activation.
    Mutagenesisi502 – 5021R → S: No effect on heterotrimerization. Greatly reduced transcriptional activation. 1 Publication
    Mutagenesisi515 – 5151R → S: Reduced heterotrimerization. 1 Publication
    Mutagenesisi519 – 5191K → R: Abolishes ubiquitination. 1 Publication

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi114500. phenotype.
    139210. phenotype.
    174900. phenotype.
    175050. phenotype.
    260350. phenotype.
    Orphaneti1333. Familial pancreatic carcinoma.
    329971. Generalized juvenile polyposis/juvenile polyposis coli.
    774. Hereditary hemorrhagic telangiectasia.
    2588. Myhre syndrome.
    PharmGKBiPA30527.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 552552Mothers against decapentaplegic homolog 4PRO_0000090861Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei37 – 371N6-acetyllysine1 Publication
    Modified residuei428 – 4281N6-acetyllysine1 Publication
    Modified residuei507 – 5071N6-acetyllysine1 Publication
    Cross-linki519 – 519Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication

    Post-translational modificationi

    Phosphorylated by PDPK1.1 Publication
    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.1 Publication

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ13485.
    PaxDbiQ13485.
    PeptideAtlasiQ13485.
    PRIDEiQ13485.

    PTM databases

    PhosphoSiteiQ13485.

    Expressioni

    Gene expression databases

    ArrayExpressiQ13485.
    BgeeiQ13485.
    CleanExiHS_SMAD4.
    GenevestigatoriQ13485.

    Organism-specific databases

    HPAiCAB002312.
    HPA019154.

    Interactioni

    Subunit structurei

    Found in a complex with SMAD1 and YY1 By similarity. Interacts with CITED2 By similarity. Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-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. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) By similarity. 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 similarity16 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    AKT1P317492EBI-347263,EBI-296087
    DACH1Q9UI363EBI-347263,EBI-347111
    DLX4Q929885EBI-347263,EBI-1752755
    FOXO3O435244EBI-347263,EBI-1644164
    GATA2P237692EBI-347263,EBI-2806671
    NLKQ9UBE86EBI-347263,EBI-366978
    SKIP127554EBI-347263,EBI-347281
    SMAD1Q157972EBI-347263,EBI-1567153
    SMAD2Q1579618EBI-347263,EBI-1040141
    SMAD3P8402217EBI-347263,EBI-347161
    SP1P080472EBI-347263,EBI-298336
    TRIM33Q9UPN96EBI-347263,EBI-2214398
    UBE2IP632794EBI-347263,EBI-80168
    USP9XQ930082EBI-347263,EBI-302524
    Usp9xP703984EBI-347263,EBI-2214043From a different organism.

    Protein-protein interaction databases

    BioGridi110264. 193 interactions.
    DIPiDIP-31512N.
    IntActiQ13485. 72 interactions.
    MINTiMINT-244037.
    STRINGi9606.ENSP00000341551.

    Structurei

    Secondary structure

    1
    552
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi288 – 2914
    Beta strandi321 – 33010
    Beta strandi333 – 34210
    Beta strandi346 – 3538
    Beta strandi359 – 3635
    Helixi364 – 3663
    Helixi374 – 3807
    Turni381 – 3855
    Beta strandi387 – 3926
    Turni393 – 3953
    Beta strandi396 – 4016
    Beta strandi403 – 4053
    Beta strandi407 – 4104
    Helixi412 – 4165
    Turni417 – 4193
    Beta strandi427 – 4293
    Beta strandi434 – 4385
    Helixi440 – 45415
    Turni455 – 4584
    Helixi493 – 4975
    Beta strandi500 – 5067
    Helixi518 – 5203
    Beta strandi521 – 5299
    Helixi530 – 54112

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1DD1X-ray2.62A/B/C285-552[»]
    1G88X-ray3.00A/B/C285-552[»]
    1MR1X-ray2.85A/B319-552[»]
    1U7FX-ray2.60B314-552[»]
    1U7VX-ray2.70B314-549[»]
    1YGSX-ray2.10A319-552[»]
    DisProtiDP00464.
    ProteinModelPortaliQ13485.
    SMRiQ13485. Positions 10-138, 285-552.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ13485.

    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.
    The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.

    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

    eggNOGiNOG286923.
    HOGENOMiHOG000286019.
    HOVERGENiHBG053353.
    InParanoidiQ13485.
    KOiK04501.
    OMAiPTEGHSI.
    OrthoDBiEOG712TW5.
    PhylomeDBiQ13485.
    TreeFamiTF314923.

    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. 1 hit.
    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.

    Q13485-1 [UniParc]FASTAAdd to Basket

    « Hide

    MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK    50
    KDELDSLITA ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR 100
    WPDLHKNELK HVKYCQYAFD LKCDSVCVNP YHYERVVSPG IDLSGLTLQS 150
    NAPSSMMVKD EYVHDFEGQP SLSTEGHSIQ TIQHPPSNRA STETYSTPAL 200
    LAPSESNATS TANFPNIPVA STSQPASILG GSHSEGLLQI ASGPQPGQQQ 250
    NGFTGQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH 300
    YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV 350
    DGYVDPSGGD RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR 400
    CLSDHAVFVQ SYYLDREAGR APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ 450
    AATAQAAAAA QAAAVAGNIP GPGSVGGIAP AISLSAAAGI GVDDLRRLCI 500
    LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL HTMPIADPQP 550
    LD 552
    Length:552
    Mass (Da):60,439
    Last modified:November 1, 1996 - v1
    Checksum:i7EE3C4647712DA90
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti13 – 131N → S.1 Publication
    Corresponds to variant rs281875323 [ dbSNP | Ensembl ].
    VAR_066870
    Natural varianti101 – 1011W → G.
    Corresponds to variant rs2229083 [ dbSNP | Ensembl ].
    VAR_052022
    Natural varianti130 – 1301P → S in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_036475
    Natural varianti330 – 3301E → G in JPS. 1 Publication
    Corresponds to variant rs281875324 [ dbSNP | Ensembl ].
    VAR_022833
    Natural varianti351 – 3511D → N in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_036476
    Natural varianti352 – 3521G → R in JP/HHT and JPS. 2 Publications
    Corresponds to variant rs121912581 [ dbSNP | Ensembl ].
    VAR_019571
    Natural varianti361 – 3611R → C in JPS. 1 Publication
    Corresponds to variant rs80338963 [ dbSNP | Ensembl ].
    VAR_019572
    Natural varianti361 – 3611R → H in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_036477
    Natural varianti386 – 3861G → D in JP/HHT. 1 Publication
    Corresponds to variant rs28936393 [ dbSNP | Ensembl ].
    VAR_019573
    Natural varianti493 – 4931D → H in pancreatic carcinoma. 1 Publication
    Corresponds to variant rs28936392 [ dbSNP | Ensembl ].
    VAR_011380
    Natural varianti500 – 5001I → M in MYHRS. 1 Publication
    Corresponds to variant rs281875320 [ dbSNP | Ensembl ].
    VAR_067602
    Natural varianti500 – 5001I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. 2 Publications
    Corresponds to variant rs281875321 [ dbSNP | Ensembl ].
    VAR_067603
    Natural varianti500 – 5001I → V in MYHRS. 2 Publications
    Corresponds to variant rs281875322 [ dbSNP | Ensembl ].
    VAR_067604

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF045447
    , AF045438, AF045439, AF045440, AF045441, AF045442, AF045443, AF045444, AF045445, AF045446 Genomic DNA. Translation: AAC03051.1.
    U44378 mRNA. Translation: AAA91041.1.
    AK290770 mRNA. Translation: BAF83459.1.
    CH471096 Genomic DNA. Translation: EAW62985.1.
    BC002379 mRNA. Translation: AAH02379.1.
    CCDSiCCDS11950.1.
    PIRiS71811.
    RefSeqiNP_005350.1. NM_005359.5.
    UniGeneiHs.75862.

    Genome annotation databases

    EnsembliENST00000342988; ENSP00000341551; ENSG00000141646.
    ENST00000398417; ENSP00000381452; ENSG00000141646.
    GeneIDi4089.
    KEGGihsa:4089.
    UCSCiuc002lfb.4. human.

    Polymorphism databases

    DMDMi13959561.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology
    Mendelian genes SMAD family member 4 (SMAD4)

    Leiden Open Variation Database (LOVD)

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF045447
    , AF045438 , AF045439 , AF045440 , AF045441 , AF045442 , AF045443 , AF045444 , AF045445 , AF045446 Genomic DNA. Translation: AAC03051.1 .
    U44378 mRNA. Translation: AAA91041.1 .
    AK290770 mRNA. Translation: BAF83459.1 .
    CH471096 Genomic DNA. Translation: EAW62985.1 .
    BC002379 mRNA. Translation: AAH02379.1 .
    CCDSi CCDS11950.1.
    PIRi S71811.
    RefSeqi NP_005350.1. NM_005359.5.
    UniGenei Hs.75862.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1DD1 X-ray 2.62 A/B/C 285-552 [» ]
    1G88 X-ray 3.00 A/B/C 285-552 [» ]
    1MR1 X-ray 2.85 A/B 319-552 [» ]
    1U7F X-ray 2.60 B 314-552 [» ]
    1U7V X-ray 2.70 B 314-549 [» ]
    1YGS X-ray 2.10 A 319-552 [» ]
    DisProti DP00464.
    ProteinModelPortali Q13485.
    SMRi Q13485. Positions 10-138, 285-552.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 110264. 193 interactions.
    DIPi DIP-31512N.
    IntActi Q13485. 72 interactions.
    MINTi MINT-244037.
    STRINGi 9606.ENSP00000341551.

    PTM databases

    PhosphoSitei Q13485.

    Polymorphism databases

    DMDMi 13959561.

    Proteomic databases

    MaxQBi Q13485.
    PaxDbi Q13485.
    PeptideAtlasi Q13485.
    PRIDEi Q13485.

    Protocols and materials databases

    DNASUi 4089.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000342988 ; ENSP00000341551 ; ENSG00000141646 .
    ENST00000398417 ; ENSP00000381452 ; ENSG00000141646 .
    GeneIDi 4089.
    KEGGi hsa:4089.
    UCSCi uc002lfb.4. human.

    Organism-specific databases

    CTDi 4089.
    GeneCardsi GC18P048494.
    GeneReviewsi SMAD4.
    HGNCi HGNC:6770. SMAD4.
    HPAi CAB002312.
    HPA019154.
    MIMi 114500. phenotype.
    139210. phenotype.
    174900. phenotype.
    175050. phenotype.
    260350. phenotype.
    600993. gene.
    neXtProti NX_Q13485.
    Orphaneti 1333. Familial pancreatic carcinoma.
    329971. Generalized juvenile polyposis/juvenile polyposis coli.
    774. Hereditary hemorrhagic telangiectasia.
    2588. Myhre syndrome.
    PharmGKBi PA30527.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG286923.
    HOGENOMi HOG000286019.
    HOVERGENi HBG053353.
    InParanoidi Q13485.
    KOi K04501.
    OMAi PTEGHSI.
    OrthoDBi EOG712TW5.
    PhylomeDBi Q13485.
    TreeFami TF314923.

    Enzyme and pathway databases

    Reactomei REACT_111057. Signaling by NODAL.
    REACT_12034. Signaling by BMP.
    REACT_120734. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_120850. TGF-beta receptor signaling activates SMADs.
    REACT_121111. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_150238. Signaling by Activin.
    REACT_169107. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_169165. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_200812. Transcriptional regulation of pluripotent stem cells.
    SignaLinki Q13485.

    Miscellaneous databases

    ChiTaRSi SMAD4. human.
    EvolutionaryTracei Q13485.
    GeneWikii Mothers_against_decapentaplegic_homolog_4.
    GenomeRNAii 4089.
    NextBioi 16030.
    PROi Q13485.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q13485.
    Bgeei Q13485.
    CleanExi HS_SMAD4.
    Genevestigatori Q13485.

    Family and domain databases

    Gene3Di 2.60.200.10. 1 hit.
    3.90.520.10. 1 hit.
    InterProi IPR013790. 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 ]
    PANTHERi PTHR13703. PTHR13703. 1 hit.
    Pfami PF03165. MH1. 1 hit.
    PF03166. MH2. 1 hit.
    [Graphical view ]
    SMARTi SM00523. DWA. 1 hit.
    SM00524. DWB. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49879. SSF49879. 1 hit.
    SSF56366. SSF56366. 1 hit.
    PROSITEi PS51075. MH1. 1 hit.
    PS51076. MH2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT PANCREATIC CARCINOMA HIS-493.
      Tissue: Fetal brain.
    2. "Receptor-associated Mad homologues synergize as effectors of the TGF-beta response."
      Zhang Y., Feng X.-H., Wu R.-Y., Derynck R.
      Nature 383:168-172(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Tissue: Placenta.
    3. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Muscle.
    7. "Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes."
      Liu F., Pouponnot C., Massague J.
      Genes Dev. 11:3157-3167(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    8. "Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors."
      Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K.
      EMBO J. 17:4056-4065(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT.
    9. "Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator."
      Shioda T., Lechleider R.J., Dunwoodie S.L., Li H., Yahata T., de Caestecker M.P., Fenner M.H., Roberts A.B., Isselbacher K.J.
      Proc. Natl. Acad. Sci. U.S.A. 95:9785-9790(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CITED1.
    10. "OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways."
      Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A., Massague J.
      Cell 100:229-240(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ZNF423.
    11. "The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain."
      de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S., Hill C.S., Shioda T., Roberts A.B., Lechleider R.J.
      J. Biol. Chem. 275:2115-2122(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF SAD DOMAIN.
    12. "LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1."
      Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M., Ashworth A.
      Hum. Mol. Genet. 10:2869-2877(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11/LKB1 AND STK11IP, INTERACTION WITH STK11/LKB1 AND STK11IP.
    13. "Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation."
      Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X.
      EMBO Rep. 3:171-176(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH COPS5.
    14. "TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling."
      Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M., Karpova T.S., McNally J.G., Roberts A.B.
      EMBO J. 22:4465-4477(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH VPS39.
    15. Cited for: INTERACTION WITH DACH1.
    16. "Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells."
      Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N., De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M., Morrone G., Venuta S.
      Blood 103:2062-2070(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ZNF521.
    17. "Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase."
      Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M., Piccolo S.
      Cell 121:87-99(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH TRIM33.
    18. "Nuclear targeting of transforming growth factor-beta-activated Smad complexes."
      Chen H.B., Rud J.G., Lin K., Xu L.
      J. Biol. Chem. 280:21329-21336(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT, SUBCELLULAR LOCATION.
    19. "Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS."
      Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., Song H., Ye Q.
      Nucleic Acids Res. 34:6314-6326(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RBPMS.
    20. "3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins."
      Seong H.A., Jung H., Kim K.T., Ha H.
      J. Biol. Chem. 282:12272-12289(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, INTERACTION WITH PDPK1.
    21. "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal."
      Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L.
      Nat. Cell Biol. 10:837-848(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH WWTR1.
    22. "FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination."
      Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L., Adorno M., Martello G., Stinchfield M.J., Soligo S., Morsut L., Inui M., Moro S., Modena N., Argenton F., Newfeld S.J., Piccolo S.
      Cell 136:123-135(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH USP9X, UBIQUITINATION, MUTAGENESIS OF LYS-519.
    23. "Lysine acetylation targets protein complexes and co-regulates major cellular functions."
      Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
      Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-37; LYS-428 AND LYS-507, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    24. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    25. Cited for: POSSIBLE INVOLVEMENT IN PULMONARY HYPERTENSION, VARIANT SER-13.
    26. "A structural basis for mutational inactivation of the tumour suppressor Smad4."
      Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P.
      Nature 388:87-93(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
    27. "Crystal structure of a transcriptionally active Smad4 fragment."
      Qin B., Lam S.S., Lin K.
      Structure 7:1493-1503(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
    28. "The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization."
      Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K.
      Nat. Struct. Biol. 8:248-253(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552 OF WILD TYPE AND MUTANTS ARG-416; ARG-502 AND ARG-515 IN COMPLEX WITH SMAD3, SUBUNIT, MUTAGENESIS OF ARG-416; ARG-502 AND ARG-515.
    29. "Structural basis of heteromeric smad protein assembly in TGF-beta signaling."
      Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J., De Caestecker M., Lin K.
      Mol. Cell 15:813-823(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 314-552 IN COMPLEX WITH SMAD2 OR SMAD3, SUBUNIT.
    30. Cited for: VARIANT JPS CYS-361.
    31. Cited for: VARIANTS JPS GLY-330 AND ARG-352.
    32. "A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)."
      Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L., Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A.
      Lancet 363:852-859(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS JP/HHT ARG-352 AND ASP-386.
    33. Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361.
    34. Cited for: VARIANTS MYHRS THR-500 AND VAL-500.
    35. Cited for: VARIANTS MYHRS MET-500; THR-500 AND VAL-500, CHARACTERIZATION OF VARIANT MYHRS THR-500.

    Entry informationi

    Entry nameiSMAD4_HUMAN
    AccessioniPrimary (citable) accession number: Q13485
    Secondary accession number(s): A8K405
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 4, 2001
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 168 of the entry and version 1 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

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 18
      Human chromosome 18: 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3