NODAL_HUMAN
ID NODAL_HUMAN Reviewed; 347 AA.
AC Q96S42; Q2M3A5; Q8N4V3;
DT 10-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT 15-JAN-2008, sequence version 2.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Nodal homolog;
DE Flags: Precursor;
GN Name=NODAL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-165.
RA Tate Genshu T.;
RT "Human Nodal-related gene.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex, and Fetal brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP VARIANT HTX5 GLN-183.
RX PubMed=9354794; DOI=10.1038/ng1197-305;
RA Gebbia M., Ferrero G.B., Pilia G., Bassi M.T., Aylsworth A.S.,
RA Penman-Splitt M., Bird L.M., Bamforth J.S., Burn J., Schlessiner D.,
RA Nelson D.L., Casey B.;
RT "X-linked situs abnormalities result from mutations in ZIC3.";
RL Nat. Genet. 17:305-308(1997).
RN [5]
RP VARIANT [LARGE SCALE ANALYSIS] LYS-279.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [6]
RP VARIANTS HTX5 LYS-203; ARG-260; CYS-275 AND PHE-284, AND CHARACTERIZATION
RP OF VARIANTS HTX5 LYS-203; ARG-260; CYS-275 AND PHE-284.
RX PubMed=19064609; DOI=10.1093/hmg/ddn411;
RA Mohapatra B., Casey B., Li H., Ho-Dawson T., Smith L., Fernbach S.D.,
RA Molinari L., Niesh S.R., Jefferies J.L., Craigen W.J., Towbin J.A.,
RA Belmont J.W., Ware S.M.;
RT "Identification and functional characterization of NODAL rare variants in
RT heterotaxy and isolated cardiovascular malformations.";
RL Hum. Mol. Genet. 18:861-871(2009).
CC -!- FUNCTION: Essential for mesoderm formation and axial patterning during
CC embryonic development. {ECO:0000250}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250}.
CC -!- INTERACTION:
CC Q96S42; Q15323: KRT31; NbExp=3; IntAct=EBI-12386190, EBI-948001;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC -!- DISEASE: Heterotaxy, visceral, 5, autosomal (HTX5) [MIM:270100]: An
CC autosomal dominant form of visceral heterotaxy, a complex disorder due
CC to disruption of the normal left-right asymmetry of the
CC thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results
CC in randomization of the placement of visceral organs, including the
CC heart, lungs, liver, spleen, and stomach. The organs are oriented
CC randomly with respect to the left-right axis and with respect to one
CC another. It can be associated with a variety of congenital defects
CC including cardiac malformations. HTX5 clinical features include situs
CC inversus viscerum or situs ambiguus, congenital heart defect,
CC transposition of the great vessels ventricular septal defect, atrial
CC septal defect, truncus communis, and dextrocardia.
CC {ECO:0000269|PubMed:19064609, ECO:0000269|PubMed:9354794}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
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DR EMBL; AB067632; BAB62524.1; -; Genomic_DNA.
DR EMBL; AC022532; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC033585; AAH33585.1; -; mRNA.
DR EMBL; BC104976; AAI04977.1; -; mRNA.
DR EMBL; BC112025; AAI12026.1; -; mRNA.
DR CCDS; CCDS7304.1; -.
DR RefSeq; NP_060525.3; NM_018055.4.
DR PDB; 4N1D; X-ray; 1.91 A; A=257-313.
DR PDBsum; 4N1D; -.
DR AlphaFoldDB; Q96S42; -.
DR SMR; Q96S42; -.
DR BioGRID; 110901; 85.
DR IntAct; Q96S42; 2.
DR STRING; 9606.ENSP00000287139; -.
DR GlyGen; Q96S42; 2 sites.
DR BioMuta; NODAL; -.
DR DMDM; 166214958; -.
DR MassIVE; Q96S42; -.
DR PaxDb; Q96S42; -.
DR PeptideAtlas; Q96S42; -.
DR PRIDE; Q96S42; -.
DR ProteomicsDB; 78063; -.
DR Antibodypedia; 29029; 325 antibodies from 35 providers.
DR DNASU; 4838; -.
DR Ensembl; ENST00000287139.8; ENSP00000287139.3; ENSG00000156574.10.
DR GeneID; 4838; -.
DR KEGG; hsa:4838; -.
DR MANE-Select; ENST00000287139.8; ENSP00000287139.3; NM_018055.5; NP_060525.3.
DR UCSC; uc001jrc.3; human.
DR CTD; 4838; -.
DR DisGeNET; 4838; -.
DR GeneCards; NODAL; -.
DR GeneReviews; NODAL; -.
DR HGNC; HGNC:7865; NODAL.
DR HPA; ENSG00000156574; Tissue enhanced (brain, skeletal muscle, testis).
DR MalaCards; NODAL; -.
DR MIM; 270100; phenotype.
DR MIM; 601265; gene.
DR neXtProt; NX_Q96S42; -.
DR OpenTargets; ENSG00000156574; -.
DR Orphanet; 93925; Alobar holoprosencephaly.
DR Orphanet; 93924; Lobar holoprosencephaly.
DR Orphanet; 280200; Microform holoprosencephaly.
DR Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly.
DR Orphanet; 220386; Semilobar holoprosencephaly.
DR Orphanet; 280195; Septopreoptic holoprosencephaly.
DR Orphanet; 157769; Situs ambiguus.
DR Orphanet; 101063; Situs inversus totalis.
DR PharmGKB; PA31669; -.
DR VEuPathDB; HostDB:ENSG00000156574; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00940000160223; -.
DR HOGENOM; CLU_020515_1_0_1; -.
DR InParanoid; Q96S42; -.
DR OMA; SWRAREG; -.
DR OrthoDB; 1518399at2759; -.
DR PhylomeDB; Q96S42; -.
DR TreeFam; TF316134; -.
DR PathwayCommons; Q96S42; -.
DR Reactome; R-HSA-1181150; Signaling by NODAL.
DR Reactome; R-HSA-1433617; Regulation of signaling by NODAL.
DR SignaLink; Q96S42; -.
DR SIGNOR; Q96S42; -.
DR BioGRID-ORCS; 4838; 9 hits in 1068 CRISPR screens.
DR GeneWiki; NODAL; -.
DR GenomeRNAi; 4838; -.
DR Pharos; Q96S42; Tbio.
DR PRO; PR:Q96S42; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q96S42; protein.
DR Bgee; ENSG00000156574; Expressed in sperm and 111 other tissues.
DR ExpressionAtlas; Q96S42; baseline and differential.
DR Genevisible; Q96S42; HS.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0016015; F:morphogen activity; NAS:BHF-UCL.
DR GO; GO:0070698; F:type I activin receptor binding; IMP:BHF-UCL.
DR GO; GO:0048327; P:axial mesodermal cell fate specification; IEA:Ensembl.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0042074; P:cell migration involved in gastrulation; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0048546; P:digestive tract morphogenesis; IEA:Ensembl.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl.
DR GO; GO:0009880; P:embryonic pattern specification; IEA:Ensembl.
DR GO; GO:0001892; P:embryonic placenta development; IEA:Ensembl.
DR GO; GO:0060136; P:embryonic process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0035987; P:endodermal cell differentiation; IMP:BHF-UCL.
DR GO; GO:0060802; P:epiblast cell-extraembryonic ectoderm cell signaling involved in anterior/posterior axis specification; IEA:Ensembl.
DR GO; GO:0033505; P:floor plate morphogenesis; IEA:Ensembl.
DR GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
DR GO; GO:0007281; P:germ cell development; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0002085; P:inhibition of neuroepithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0060460; P:left lung morphogenesis; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0001893; P:maternal placenta development; IEA:Ensembl.
DR GO; GO:0060137; P:maternal process involved in parturition; IEA:Ensembl.
DR GO; GO:0048382; P:mesendoderm development; IMP:BHF-UCL.
DR GO; GO:0060766; P:negative regulation of androgen receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0010721; P:negative regulation of cell development; IEA:Ensembl.
DR GO; GO:1901383; P:negative regulation of chorionic trophoblast cell proliferation; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:1901164; P:negative regulation of trophoblast cell migration; IDA:BHF-UCL.
DR GO; GO:0001842; P:neural fold formation; IEA:Ensembl.
DR GO; GO:1900164; P:nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry; IEA:Ensembl.
DR GO; GO:0001890; P:placenta development; IMP:BHF-UCL.
DR GO; GO:0010085; P:polarity specification of proximal/distal axis; IEA:Ensembl.
DR GO; GO:0032927; P:positive regulation of activin receptor signaling pathway; IGI:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0022409; P:positive regulation of cell-cell adhesion; IMP:BHF-UCL.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:BHF-UCL.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IDA:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL.
DR GO; GO:1900224; P:positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry; ISS:BHF-UCL.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IMP:BHF-UCL.
DR GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:BHF-UCL.
DR GO; GO:0010470; P:regulation of gastrulation; IEA:Ensembl.
DR GO; GO:2000036; P:regulation of stem cell population maintenance; TAS:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl.
DR GO; GO:0090010; P:transforming growth factor beta receptor signaling pathway involved in primitive streak formation; IEA:Ensembl.
DR GO; GO:0001831; P:trophectodermal cellular morphogenesis; IEA:Ensembl.
DR GO; GO:0001944; P:vasculature development; IEA:Ensembl.
DR Gene3D; 2.10.90.10; -; 1.
DR IDEAL; IID00577; -.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR017948; TGFb_CS.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cleavage on pair of basic residues; Cytokine;
KW Developmental protein; Disease variant; Disulfide bond; Glycoprotein;
KW Growth factor; Heterotaxy; Reference proteome; Secreted; Signal.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT PROPEP 27..237
FT /evidence="ECO:0000255"
FT /id="PRO_0000033998"
FT CHAIN 238..347
FT /note="Nodal homolog"
FT /id="PRO_0000033999"
FT CARBOHYD 72
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 199
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 247..313
FT /evidence="ECO:0000250"
FT DISULFID 276..344
FT /evidence="ECO:0000250"
FT DISULFID 280..346
FT /evidence="ECO:0000250"
FT DISULFID 312
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT VARIANT 165
FT /note="H -> R (in dbSNP:rs1904589)"
FT /evidence="ECO:0000269|Ref.1"
FT /id="VAR_038193"
FT VARIANT 183
FT /note="R -> Q (in HTX5; dbSNP:rs104894169)"
FT /evidence="ECO:0000269|PubMed:9354794"
FT /id="VAR_015111"
FT VARIANT 203
FT /note="E -> K (in HTX5; likely benign variant; decrease in
FT signal transduction; dbSNP:rs10999334)"
FT /evidence="ECO:0000269|PubMed:19064609"
FT /id="VAR_038194"
FT VARIANT 260
FT /note="G -> R (in HTX5; decrease in signal transduction;
FT dbSNP:rs121909283)"
FT /evidence="ECO:0000269|PubMed:19064609"
FT /id="VAR_062281"
FT VARIANT 275
FT /note="R -> C (in HTX5; decrease in signal transduction;
FT dbSNP:rs781366461)"
FT /evidence="ECO:0000269|PubMed:19064609"
FT /id="VAR_062282"
FT VARIANT 279
FT /note="E -> K (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs755116310)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036202"
FT VARIANT 284
FT /note="V -> F (in HTX5; decrease in signal transduction;
FT dbSNP:rs1310479365)"
FT /evidence="ECO:0000269|PubMed:19064609"
FT /id="VAR_062283"
FT TURN 257..260
FT /evidence="ECO:0007829|PDB:4N1D"
FT TURN 262..264
FT /evidence="ECO:0007829|PDB:4N1D"
FT STRAND 265..267
FT /evidence="ECO:0007829|PDB:4N1D"
FT STRAND 269..272
FT /evidence="ECO:0007829|PDB:4N1D"
FT STRAND 275..279
FT /evidence="ECO:0007829|PDB:4N1D"
FT HELIX 286..288
FT /evidence="ECO:0007829|PDB:4N1D"
FT HELIX 292..303
FT /evidence="ECO:0007829|PDB:4N1D"
FT TURN 305..307
FT /evidence="ECO:0007829|PDB:4N1D"
SQ SEQUENCE 347 AA; 39561 MW; 0D52352B9711650C CRC64;
MHAHCLPFLL HAWWALLQAG AATVATALLR TRGQPSSPSP LAYMLSLYRD PLPRADIIRS
LQAEDVAVDG QNWTFAFDFS FLSQQEDLAW AELRLQLSSP VDLPTEGSLA IEIFHQPKPD
TEQASDSCLE RFQMDLFTVT LSQVTFSLGS MVLEVTRPLS KWLKHPGALE KQMSRVAGEC
WPRPPTPPAT NVLLMLYSNL SQEQRQLGGS TLLWEAESSW RAQEGQLSWE WGKRHRRHHL
PDRSQLCRKV KFQVDFNLIG WGSWIIYPKQ YNAYRCEGEC PNPVGEEFHP TNHAYIQSLL
KRYQPHRVPS TCCAPVKTKP LSMLYVDNGR VLLDHHKDMI VEECGCL
