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   13-FEB-2019, entry version 124.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; 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
RT   distinct 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
RT   onto transcripts of the GNAS gene and posttranslational processing of
RT   a 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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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.,
RA   Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA   Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA   Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA   Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA   Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA   Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA   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.,
RA   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
RT   uncoupling 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.,
RA   Levine M.A.;
RT   "Discordance between genetic and epigenetic defects in
RT   pseudohypoparathyroidism type 1b revealed by inconsistent loss of
RT   maternal 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.,
RA   Pereira M.A.A., 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/JCI19159;
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.,
RA   Slyper A.H., Sugimoto T., Tsatsoulis A., Crawford J.D., Jueppner H.;
RT   "Autosomal dominant pseudohypoparathyroidism type Ib is associated
RT   with a heterozygous microdeletion that likely disrupts a putative
RT   imprinting 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
RT   type Ib redefines the boundaries of a cis-acting imprinting control
RT   element of 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
RT   of 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
CC       secretory granules. {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=8;
CC       Name=Nesp55 {ECO:0000269|PubMed:10729789,
CC       ECO:0000269|PubMed:10749992, ECO:0000269|PubMed:9860993,
CC       ECO:0000269|Ref.4};
CC         IsoId=O95467-1; Sequence=Displayed;
CC         Note=Shares no sequence similarity with other isoforms due to a
CC         novel first exon containing the entire reading frame spliced to
CC         shared exon 2 so that exons 2-13 make up the 3'-UTR.;
CC       Name=XLas-1;
CC         IsoId=Q5JWF2-1; Sequence=External;
CC         Note=Gene prediction confirmed by EST data.;
CC       Name=XLas-2;
CC         IsoId=Q5JWF2-2; Sequence=External;
CC         Note=Gene prediction confirmed by EST data.;
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         Note=No experimental confirmation available.;
CC       Name=4;
CC         IsoId=P63092-4; Sequence=External;
CC         Note=Gene prediction based on EST data.;
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
CC       (AIMAH1) [MIM:219080]: A rare adrenal defect characterized by
CC       multiple, bilateral, non-pigmented, benign, adrenocortical
CC       nodules. It results in excessive production of cortisol leading to
CC       ACTH-independent Cushing syndrome. Clinical manifestations of
CC       Cushing syndrome include facial and truncal obesity, abdominal
CC       striae, muscular weakness, osteoporosis, arterial hypertension,
CC       diabetes. {ECO:0000269|PubMed:12727968}. Note=The disease is
CC       caused by mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A
CC       disorder characterized by end-organ resistance to parathyroid
CC       hormone, hypocalcemia and hyperphosphatemia. Patients affected
CC       with PHP1B lack developmental defects characteristic of Albright
CC       hereditary osteodystrophy, and typically show no other endocrine
CC       abnormalities besides resistance to PTH.
CC       {ECO:0000269|PubMed:11029463, ECO:0000269|PubMed:11067869,
CC       ECO:0000269|PubMed:11294659, ECO:0000269|PubMed:12858292,
CC       ECO:0000269|PubMed:14561710, ECO:0000269|PubMed:15592469,
CC       ECO:0000269|PubMed:15800843}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry. Most
CC       affected individuals have defects in methylation of the gene. In
CC       some cases microdeletions involving the STX16 appear to cause loss
CC       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
CC       is characterized by increased trauma-related bleeding tendency,
CC       prolonged bleeding time, brachydactyly and mental retardation.
CC       Both the XLas isoforms and the ALEX protein are mutated which
CC       strongly reduces the interaction between them and this may allow
CC       unimpeded activation of the XLas isoforms. Note=The disease is
CC       caused by mutations affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: This protein is produced by a bicistronic gene
CC       which also produces the ALEX protein from an overlapping reading
CC       frame. {ECO:0000305}.
CC   -!- MISCELLANEOUS: The GNAS locus is imprinted in a complex manner,
CC       giving rise to distinct paternally, maternally and biallelically
CC       expressed proteins. The XLas isoforms are paternally derived, the
CC       Gnas isoforms are biallelically derived and the Nesp55 isoforms
CC       are maternally derived.
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   UniGene; Hs.125898; -.
DR   ProteinModelPortal; O95467; -.
DR   SMR; O95467; -.
DR   BioGrid; 109040; 104.
DR   iPTMnet; O95467; -.
DR   BioMuta; GNAS; -.
DR   EPD; O95467; -.
DR   PeptideAtlas; O95467; -.
DR   PRIDE; O95467; -.
DR   ProteomicsDB; 50901; -.
DR   DNASU; 2778; -.
DR   Ensembl; ENST00000313949; ENSP00000323571; ENSG00000087460. [O95467-1]
DR   Ensembl; ENST00000371075; ENSP00000360115; ENSG00000087460. [O95467-1]
DR   Ensembl; ENST00000371098; ENSP00000360139; ENSG00000087460. [O95467-1]
DR   GeneID; 2778; -.
DR   KEGG; hsa:2778; -.
DR   UCSC; uc002xzt.5; human. [O95467-1]
DR   CTD; 2778; -.
DR   DisGeNET; 2778; -.
DR   EuPathDB; HostDB:ENSG00000087460.23; -.
DR   GeneCards; GNAS; -.
DR   GeneReviews; GNAS; -.
DR   HGNC; HGNC:4392; GNAS.
DR   HPA; CAB010337; -.
DR   HPA; HPA018122; -.
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   GeneTree; ENSGT00940000156300; -.
DR   HOGENOM; HOG000276539; -.
DR   HOVERGEN; HBG081561; -.
DR   KO; K04632; -.
DR   OrthoDB; 754573at2759; -.
DR   ChiTaRS; GNAS; human.
DR   GeneWiki; GNAS_complex_locus; -.
DR   GenomeRNAi; 2778; -.
DR   Proteomes; UP000005640; Chromosome 20.
DR   Bgee; ENSG00000087460; Expressed in 252 organ(s), highest expression level in telencephalon.
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:UniProtKB.
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;
KW   Complete proteome; Cushing syndrome; Cytoplasmic vesicle;
KW   Glycoprotein; Proteoglycan; Reference proteome; Secreted; Signal.
FT   SIGNAL        1     46       {ECO:0000250}.
FT   CHAIN        47    245       Neuroendocrine secretory protein 55.
FT                                /FTId=PRO_0000253967.
FT   PEPTIDE     163    166       LHAL tetrapeptide. {ECO:0000255,
FT                                ECO:0000303|PubMed:10729789}.
FT                                /FTId=PRO_0000253968.
FT   PEPTIDE     238    245       GPIPIRRH peptide. {ECO:0000255,
FT                                ECO:0000303|PubMed:10729789}.
FT                                /FTId=PRO_0000253969.
FT   COMPBIAS     78    142       Glu-rich. {ECO:0000255}.
FT   CONFLICT     26     26       R -> C (in Ref. 4; AAD11804).
FT                                {ECO:0000305}.
FT   CONFLICT     41     41       L -> D (in Ref. 4; AAD11804).
FT                                {ECO:0000305}.
FT   CONFLICT     72     72       G -> GR (in Ref. 4; AAD11804).
FT                                {ECO:0000305}.
FT   CONFLICT    133    133       P -> PETAP (in Ref. 4). {ECO:0000305}.
FT   CONFLICT    171    171       P -> A (in Ref. 4; AAD11804).
FT                                {ECO:0000305}.
FT   CONFLICT    211    219       KEEKQRRRC -> REENSSDSS (in Ref. 4;
FT                                AAD11804). {ECO:0000305}.
FT   CONFLICT    230    230       S -> F (in Ref. 4; AAD11804).
FT                                {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
//