GNAS3_HUMAN
ID GNAS3_HUMAN Reviewed; 245 AA.
AC O95467; B2RB88; E1P5G2; O95417;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Neuroendocrine secretory protein 55;
DE Short=NESP55;
DE Contains:
DE RecName: Full=LHAL tetrapeptide;
DE Contains:
DE RecName: Full=GPIPIRRH peptide;
DE Flags: Precursor;
GN Name=GNAS {ECO:0000312|HGNC:HGNC:4392};
GN Synonyms=GNAS1 {ECO:0000312|EMBL:CAA08889.1};
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] {ECO:0000312|EMBL:CAA08889.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9860993; DOI=10.1073/pnas.95.26.15475;
RA Hayward B.E., Moran V., Strain L., Bonthron D.T.;
RT "Bidirectional imprinting of a single gene: human GNAS1 encodes distinct
RT maternally, paternally and biallelically derived proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:15475-15480(1998).
RN [2] {ECO:0000312|EMBL:CAB83214.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10749992; DOI=10.1093/hmg/9.5.835;
RA Hayward B.E., Bonthron D.T.;
RT "An imprinted antisense transcript at the human GNAS1 locus.";
RL Hum. Mol. Genet. 9:835-841(2000).
RN [3] {ECO:0000312|EMBL:AAF63226.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10729789; DOI=10.1159/000054535;
RA Weiss U., Ischia R., Eder S., Lovisetti-Scamihorn P., Bauer R.,
RA Fischer-Colbrie R.;
RT "Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto
RT transcripts of the GNAS gene and posttranslational processing of a
RT maternally expressed protein.";
RL Neuroendocrinology 71:177-186(2000).
RN [4] {ECO:0000312|EMBL:AAD11804.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Wang Y.Z., Kehlenbach R.H., Huttner W.B.;
RT "Molecular characterization of XL2, a neuroendocrine-specific luminal
RT Golgi-resident protein.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6] {ECO:0000312|EMBL:AAD11804.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11067869; DOI=10.1172/jci10431;
RA Liu J., Litman D., Rosenberg M.J., Yu S., Biesecker L.G., Weinstein L.S.;
RT "A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.";
RL J. Clin. Invest. 106:1167-1174(2000).
RN [8]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11294659; DOI=10.1086/320117;
RA Bastepe M., Lane A.H., Jueppner H.;
RT "Paternal uniparental isodisomy of chromosome 20q -- and the resulting
RT changes in GNAS1 methylation -- as a plausible cause of
RT pseudohypoparathyroidism.";
RL Am. J. Hum. Genet. 68:1283-1289(2001).
RN [9]
RP INVOLVEMENT IN PHP1B.
RX PubMed=11029463; DOI=10.1074/jbc.m006032200;
RA Wu W.-I., Schwindinger W.F., Aparicio L.F., Levine M.A.;
RT "Selective resistance to parathyroid hormone caused by a novel uncoupling
RT mutation in the carboxyl terminus of G alpha(s). A cause of
RT pseudohypoparathyroidism type Ib.";
RL J. Biol. Chem. 276:165-171(2001).
RN [10]
RP INVOLVEMENT IN PHP1B.
RX PubMed=12858292; DOI=10.1086/377136;
RA Jan de Beur S., Ding C., Germain-Lee E., Cho J., Maret A., Levine M.A.;
RT "Discordance between genetic and epigenetic defects in
RT pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal
RT imprinting at GNAS1.";
RL Am. J. Hum. Genet. 73:314-322(2003).
RN [11]
RP INVOLVEMENT IN AIMAH1.
RX PubMed=12727968; DOI=10.1210/jc.2002-021362;
RA Fragoso M.C.B.V., Domenice S., Latronico A.C., Martin R.M., Pereira M.A.A.,
RA Zerbini M.C.N., Lucon A.M., Mendonca B.B.;
RT "Cushing's syndrome secondary to adrenocorticotropin-independent
RT macronodular adrenocortical hyperplasia due to activating mutations of
RT GNAS1 gene.";
RL J. Clin. Endocrinol. Metab. 88:2147-2151(2003).
RN [12]
RP INVOLVEMENT IN PHP1B.
RX PubMed=14561710; DOI=10.1172/jci200319159;
RA Bastepe M., Froehlich L.F., Hendy G.N., Indridason O.S., Josse R.G.,
RA Koshiyama H., Koerkkoe J., Nakamoto J.M., Rosenbloom A.L., Slyper A.H.,
RA Sugimoto T., Tsatsoulis A., Crawford J.D., Jueppner H.;
RT "Autosomal dominant pseudohypoparathyroidism type Ib is associated with a
RT heterozygous microdeletion that likely disrupts a putative imprinting
RT control element of GNAS.";
RL J. Clin. Invest. 112:1255-1263(2003).
RN [13]
RP INVOLVEMENT IN PHP1B.
RX PubMed=15800843; DOI=10.1086/429932;
RA Linglart A., Gensure R.C., Olney R.C., Jueppner H., Bastepe M.;
RT "A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type
RT Ib redefines the boundaries of a cis-acting imprinting control element of
RT GNAS.";
RL Am. J. Hum. Genet. 76:804-814(2005).
RN [14]
RP INVOLVEMENT IN PHP1B.
RX PubMed=15592469; DOI=10.1038/ng1487;
RA Bastepe M., Froehlich L.F., Linglart A., Abu-Zahra H.S., Tojo K.,
RA Ward L.M., Jueppner H.;
RT "Deletion of the NESP55 differentially methylated region causes loss of
RT maternal GNAS imprints and pseudohypoparathyroidism type Ib.";
RL Nat. Genet. 37:25-27(2005).
CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle
CC {ECO:0000250}. Secreted {ECO:0000250}. Note=Neuroendocrine secretory
CC granules. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=Nesp55 {ECO:0000269|PubMed:10729789, ECO:0000269|PubMed:10749992,
CC ECO:0000269|PubMed:9860993, ECO:0000269|Ref.4};
CC IsoId=O95467-1; Sequence=Displayed;
CC Name=XLas-1;
CC IsoId=Q5JWF2-1; Sequence=External;
CC Name=XLas-2;
CC IsoId=Q5JWF2-2; Sequence=External;
CC Name=XLas-3;
CC IsoId=Q5JWF2-3; Sequence=External;
CC Name=Gnas-1 {ECO:0000305}; Synonyms=Alpha-S2 {ECO:0000305}, GNASl
CC {ECO:0000305}, Alpha-S-long {ECO:0000305};
CC IsoId=P63092-1, P04895-1;
CC Sequence=External;
CC Name=Gnas-2 {ECO:0000305}; Synonyms=Alpha-S1 {ECO:0000305}, GNASs
CC {ECO:0000305}, Alpha-S-short {ECO:0000305};
CC IsoId=P63092-2, P04895-2;
CC Sequence=External;
CC Name=3;
CC IsoId=P63092-3; Sequence=External;
CC Name=4;
CC IsoId=P63092-4; Sequence=External;
CC -!- PTM: Binds keratan sulfate chains. {ECO:0000250|UniProtKB:O18979}.
CC -!- PTM: May be proteolytically processed to give rise to a number of
CC active peptides. {ECO:0000269|PubMed:10729789}.
CC -!- DISEASE: ACTH-independent macronodular adrenal hyperplasia 1 (AIMAH1)
CC [MIM:219080]: A rare adrenal defect characterized by multiple,
CC bilateral, non-pigmented, benign, adrenocortical nodules. It results in
CC excessive production of cortisol leading to ACTH-independent Cushing
CC syndrome. Clinical manifestations of Cushing syndrome include facial
CC and truncal obesity, abdominal striae, muscular weakness, osteoporosis,
CC arterial hypertension, diabetes. {ECO:0000269|PubMed:12727968}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A disorder
CC characterized by end-organ resistance to parathyroid hormone,
CC hypocalcemia and hyperphosphatemia. Patients affected with PHP1B lack
CC developmental defects characteristic of Albright hereditary
CC osteodystrophy, and typically show no other endocrine abnormalities
CC besides resistance to PTH. {ECO:0000269|PubMed:11029463,
CC ECO:0000269|PubMed:11067869, ECO:0000269|PubMed:11294659,
CC ECO:0000269|PubMed:12858292, ECO:0000269|PubMed:14561710,
CC ECO:0000269|PubMed:15592469, ECO:0000269|PubMed:15800843}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. Most affected individuals have defects in methylation of the
CC gene. In some cases microdeletions involving the STX16 appear to cause
CC loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal
CC uniparental isodisomy have also been observed.
CC -!- DISEASE: GNAS hyperfunction (GNASHYP) [MIM:139320]: This condition is
CC characterized by increased trauma-related bleeding tendency, prolonged
CC bleeding time, brachydactyly and intellectual disability. Both the XLas
CC isoforms and the ALEX protein are mutated which strongly reduces the
CC interaction between them and this may allow unimpeded activation of the
CC XLas isoforms. Note=The disease is caused by variants affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: This protein is produced by a bicistronic gene which
CC also produces the ALEX protein from an overlapping reading frame.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: The GNAS locus is imprinted in a complex manner, giving
CC rise to distinct paternally, maternally and biallelically expressed
CC proteins. The XLas isoforms are paternally derived, the Gnas isoforms
CC are biallelically derived and the Nesp55 isoforms are maternally
CC derived.
CC -!- MISCELLANEOUS: [Isoform Nesp55]: Shares no sequence similarity with
CC other isoforms due to a novel first exon containing the entire reading
CC frame spliced to shared exon 2 so that exons 2-13 make up the 3'-UTR.
CC -!- SIMILARITY: Belongs to the NESP55 family. {ECO:0000255}.
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DR EMBL; AJ009849; CAA08889.1; -; Genomic_DNA.
DR EMBL; AJ251760; CAB83214.1; -; Genomic_DNA.
DR EMBL; AF105253; AAF63226.1; -; mRNA.
DR EMBL; AF107846; AAD11804.1; -; Genomic_DNA.
DR EMBL; AK314549; BAG37135.1; -; mRNA.
DR EMBL; CH471077; EAW75466.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75457.1; -; Genomic_DNA.
DR CCDS; CCDS13471.1; -. [O95467-1]
DR RefSeq; NP_000507.1; NM_000516.5.
DR RefSeq; NP_001070956.1; NM_001077488.3.
DR RefSeq; NP_001070957.1; NM_001077489.3.
DR RefSeq; NP_001296790.1; NM_001309861.1.
DR RefSeq; NP_057676.1; NM_016592.3. [O95467-1]
DR RefSeq; NP_536351.1; NM_080426.3.
DR RefSeq; XP_016883310.1; XM_017027821.1. [O95467-1]
DR RefSeq; XP_016883311.1; XM_017027822.1. [O95467-1]
DR AlphaFoldDB; O95467; -.
DR SMR; O95467; -.
DR BioGRID; 109040; 213.
DR IntAct; O95467; 1.
DR iPTMnet; O95467; -.
DR BioMuta; GNAS; -.
DR MassIVE; O95467; -.
DR PeptideAtlas; O95467; -.
DR PRIDE; O95467; -.
DR ProteomicsDB; 50901; -. [O95467-1]
DR Antibodypedia; 4152; 809 antibodies from 44 providers.
DR DNASU; 2778; -.
DR Ensembl; ENST00000313949.11; ENSP00000323571.7; ENSG00000087460.29. [O95467-1]
DR Ensembl; ENST00000371075.7; ENSP00000360115.3; ENSG00000087460.29. [O95467-1]
DR Ensembl; ENST00000371098.6; ENSP00000360139.2; ENSG00000087460.29. [O95467-1]
DR Ensembl; ENST00000419558.7; ENSP00000416234.2; ENSG00000087460.29. [O95467-1]
DR Ensembl; ENST00000453292.7; ENSP00000392000.2; ENSG00000087460.29. [O95467-1]
DR GeneID; 2778; -.
DR KEGG; hsa:2778; -.
DR UCSC; uc002xzt.5; human. [O95467-1]
DR CTD; 2778; -.
DR DisGeNET; 2778; -.
DR GeneCards; GNAS; -.
DR GeneReviews; GNAS; -.
DR HGNC; HGNC:4392; GNAS.
DR HPA; ENSG00000087460; Low tissue specificity.
DR MalaCards; GNAS; -.
DR MIM; 139320; gene+phenotype.
DR MIM; 219080; phenotype.
DR MIM; 603233; phenotype.
DR neXtProt; NX_O95467; -.
DR OpenTargets; ENSG00000087460; -.
DR PharmGKB; PA175; -.
DR VEuPathDB; HostDB:ENSG00000087460; -.
DR GeneTree; ENSGT00940000156300; -.
DR HOGENOM; CLU_100255_0_0_1; -.
DR OrthoDB; 754573at2759; -.
DR PathwayCommons; O95467; -.
DR BioGRID-ORCS; 2778; 28 hits in 1092 CRISPR screens.
DR ChiTaRS; GNAS; human.
DR GeneWiki; GNAS_complex_locus; -.
DR GenomeRNAi; 2778; -.
DR Pharos; O95467; Tbio.
DR Proteomes; UP000005640; Chromosome 20.
DR Bgee; ENSG00000087460; Expressed in type B pancreatic cell and 213 other tissues.
DR ExpressionAtlas; O95467; baseline and differential.
DR Genevisible; O95467; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0030133; C:transport vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0007565; P:female pregnancy; NAS:UniProtKB.
DR GO; GO:0040015; P:negative regulation of multicellular organism growth; ISS:CAFA.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0009306; P:protein secretion; NAS:UniProtKB.
DR GO; GO:0071107; P:response to parathyroid hormone; IMP:UniProtKB.
DR InterPro; IPR009434; NESP55.
DR Pfam; PF06390; NESP55; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Cleavage on pair of basic residues; Cushing syndrome;
KW Cytoplasmic vesicle; Glycoprotein; Proteoglycan; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..46
FT /evidence="ECO:0000250"
FT CHAIN 47..245
FT /note="Neuroendocrine secretory protein 55"
FT /id="PRO_0000253967"
FT PEPTIDE 163..166
FT /note="LHAL tetrapeptide"
FT /evidence="ECO:0000255, ECO:0000303|PubMed:10729789"
FT /id="PRO_0000253968"
FT PEPTIDE 238..245
FT /note="GPIPIRRH peptide"
FT /evidence="ECO:0000255, ECO:0000303|PubMed:10729789"
FT /id="PRO_0000253969"
FT REGION 70..245
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 80..95
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 96..137
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 188..216
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CONFLICT 26
FT /note="R -> C (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
FT CONFLICT 41
FT /note="L -> D (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
FT CONFLICT 72
FT /note="G -> GR (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
FT CONFLICT 133
FT /note="P -> PETAP (in Ref. 4)"
FT /evidence="ECO:0000305"
FT CONFLICT 171
FT /note="P -> A (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
FT CONFLICT 211..219
FT /note="KEEKQRRRC -> REENSSDSS (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
FT CONFLICT 230
FT /note="S -> F (in Ref. 4; AAD11804)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 245 AA; 28029 MW; 4F02B8B1115089E2 CRC64;
MDRRSRAQQW RRARHNYNDL CPPIGRRAAT ALLWLSCSIA LLRALATSNA RAQQRAAAQQ
RRSFLNAHHR SGAQVFPESP ESESDHEHEE ADLELSLPEC LEYEEEFDYE TESETESEIE
SETDFETEPE TAPTTEPETE PEDDRGPVVP KHSTFGQSLT QRLHALKLRS PDASPSRAPP
STQEPQSPRE GEELKPEDKD PRDPEESKEP KEEKQRRRCK PKKPTRRDAS PESPSKKGPI
PIRRH
