ID IAPP_HUMAN Reviewed; 89 AA. AC P10997; Q0ZD87; Q14598; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 09-DEC-2015, entry version 158. DE RecName: Full=Islet amyloid polypeptide; DE AltName: Full=Amylin; DE AltName: Full=Diabetes-associated peptide; DE Short=DAP; DE AltName: Full=Insulinoma amyloid peptide; DE Flags: Precursor; GN Name=IAPP; 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] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND AMIDATION AT TYR-70. RX PubMed=2651160; DOI=10.1016/0014-5793(89)81260-8; RA Mosselman S., Hoeppener J.W.M., Lips C.J.M., Jansz H.S.; RT "The complete islet amyloid polypeptide precursor is encoded by two RT exons."; RL FEBS Lett. 247:154-158(1989). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2608057; DOI=10.1210/mend-3-11-1775; RA Nishi M., Sanke T., Seino S., Eddy R.L., Fan Y.-S., Byers M.G., RA Shows T.B., Bell G.I., Steiner D.F.; RT "Human islet amyloid polypeptide gene: complete nucleotide sequence, RT chromosomal localization, and evolutionary history."; RL Mol. Endocrinol. 3:1775-1781(1989). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=3053705; RA Sanke T., Bell G.I., Sample C., Rubenstein A.H., Steiner D.F.; RT "An islet amyloid peptide is derived from an 89-amino acid precursor RT by proteolytic processing."; RL J. Biol. Chem. 263:17243-17246(1988). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2365085; DOI=10.1016/0014-5793(90)80314-9; RA Christmanson L., Rorsman F., Stenman G., Westermark P., Betsholtz C.; RT "The human islet amyloid polypeptide (IAPP) gene. Organization, RT chromosomal localization and functional identification of a promoter RT region."; RL FEBS Lett. 267:160-166(1990). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2223885; DOI=10.1016/0167-4781(90)90210-S; RA van Mansfeld A.D.M., Mosselman S., Hoeppener J.W.M., Zandberg J., RA van Teeffelen H.A.A.M., Baas P.D., Lips C.J.M., Jansz H.S.; RT "Islet amyloid polypeptide: structure and upstream sequences of the RT IAPP gene in rat and man."; RL Biochim. Biophys. Acta 1087:235-240(1990). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=1282806; DOI=10.1016/0006-291X(92)90255-J; RA Hoeppener J.W.M., Oosterwijk C., Visser-Vernooy H.J., Lips C.J.M., RA Jansz H.S.; RT "Characterization of the human islet amyloid polypeptide/amylin gene RT transcripts: identification of a new polyadenylation site."; RL Biochem. Biophys. Res. Commun. 189:1569-1577(1992). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, DOMAIN, AND MASS RP SPECTROMETRY. RC TISSUE=Fetal pancreas; RX PubMed=17374526; DOI=10.1016/j.bbrc.2007.03.016; RA Bhattacharya S., Naveena Lavanya Latha J., Kumresan R., Singh S.; RT "Cloning and expression of human islet amyloid polypeptide in cultured RT cells."; RL Biochem. Biophys. Res. Commun. 356:622-628(2007). RN [8] 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-89. RX PubMed=3181427; DOI=10.1016/0014-5793(88)80922-0; RA Mosselman S., Hoeppener J.W.M., Zandberg J., van Mansfeld A.D.M., RA Geurts van Kessel A.H.M., Lips C.J.M., Jansz H.S.; RT "Islet amyloid polypeptide: identification and chromosomal RT localization of the human gene."; RL FEBS Lett. 239:227-232(1988). RN [10] RP PROTEIN SEQUENCE OF 34-70, AND DISULFIDE BOND. RX PubMed=3317417; DOI=10.1073/pnas.84.23.8628; RA Cooper G.J., Willis A.C., Clark A., Turner R.C., Sim R.B., Reid K.B.; RT "Purification and characterization of a peptide from amyloid-rich RT pancreases of type 2 diabetic patients."; RL Proc. Natl. Acad. Sci. U.S.A. 84:8628-8632(1987). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-70, AND SYNTHESIS OF 53-62. RX PubMed=2666169; DOI=10.1016/0014-5793(89)81467-X; RA Betsholtz C., Christmansson L., Engstroem U., Rorsman F., Svensson V., RA Johnson K.H., Westermark P.; RT "Sequence divergence in a specific region of islet amyloid polypeptide RT (IAPP) explains differences in islet amyloid formation between RT species."; RL FEBS Lett. 251:261-264(1989). RN [12] RP PROTEIN SEQUENCE OF 34-70. RX PubMed=2091067; DOI=10.1016/0167-0115(90)90004-G; RA Nakazato M., Asai J., Miyazato M., Matsukura S., Kangawa K., RA Matsuo H.; RT "Isolation and identification of islet amyloid polypeptide in normal RT human pancreas."; RL Regul. Pept. 31:179-186(1990). RN [13] RP PROTEIN SEQUENCE OF 34-52. RX PubMed=3535798; DOI=10.1016/0006-291X(86)90708-4; RA Westermark P., Wernstedt C., Wilander E., Sletten K.; RT "A novel peptide in the calcitonin gene related peptide family as an RT amyloid fibril protein in the endocrine pancreas."; RL Biochem. Biophys. Res. Commun. 140:827-831(1986). RN [14] RP PROTEIN SEQUENCE OF 34-70. RX PubMed=3035556; DOI=10.1073/pnas.84.11.3881; RA Westermark P., Wernstedt C., Wilander E., Hayden D.W., O'Brien T.D., RA Johnson K.H.; RT "Amyloid fibrils in human insulinoma and islets of Langerhans of the RT diabetic cat are derived from a neuropeptide-like protein also present RT in normal islet cells."; RL Proc. Natl. Acad. Sci. U.S.A. 84:3881-3885(1987). RN [15] RP PROTEIN SEQUENCE OF 30-89. RX PubMed=2690069; DOI=10.1073/pnas.86.24.9662; RA Roberts A.N., Leighton B., Todd J.A., Cockburn D., Schofield P.N., RA Sutton R., Holt S., Boyd Y., Day A.J., Foot E.A., Willis A.C., RA Reid K.B.M., Cooper G.J.S.; RT "Molecular and functional characterization of amylin, a peptide RT associated with type 2 diabetes mellitus."; RL Proc. Natl. Acad. Sci. U.S.A. 86:9662-9666(1989). RN [16] RP STRUCTURE BY NMR OF IAPP. RX PubMed=2039456; RA Hubbard J.A.M., Martin S.R., Chaplin L.C., Bose C., Kelly S.M., RA Price N.C.; RT "Solution structures of calcitonin-gene-related-peptide analogues of RT calcitonin-gene-related peptide and amylin."; RL Biochem. J. 275:785-788(1991). RN [17] RP STRUCTURE BY NMR OF 53-62 IN DETERGENT MICELLES. RX PubMed=12717720; DOI=10.1002/bip.10305; RA Mascioni A., Porcelli F., Ilangovan U., Ramamoorthy A., Veglia G.; RT "Conformational preferences of the amylin nucleation site in SDS RT micelles: an NMR study."; RL Biopolymers 69:29-41(2003). RN [18] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 34-70 IN COMPLEX WITH IDE, RP AND INTERACTION WITH IDE. RX PubMed=17051221; DOI=10.1038/nature05143; RA Shen Y., Joachimiak A., Rosner M.R., Tang W.-J.; RT "Structures of human insulin-degrading enzyme reveal a new substrate RT recognition mechanism."; RL Nature 443:870-874(2006). RN [19] RP STRUCTURE BY NMR OF 34-70 IN DETERGENT MICELLES, DOMAIN, AND DISULFIDE RP BOND. RX PubMed=19244249; DOI=10.1074/jbc.M809085200; RA Patil S.M., Xu S., Sheftic S.R., Alexandrescu A.T.; RT "Dynamic alpha-helix structure of micelle-bound human amylin."; RL J. Biol. Chem. 284:11982-11991(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) IN COMPLEX WITH INS, DISULFIDE RP BOND, MUTAGENESIS OF PHE-48, AND DOMAIN. RX PubMed=19475663; DOI=10.1002/pro.145; RA Wiltzius J.J., Sievers S.A., Sawaya M.R., Eisenberg D.; RT "Atomic structures of IAPP (amylin) fusions suggest a mechanism for RT fibrillation and the role of insulin in the process."; RL Protein Sci. 18:1521-1530(2009). RN [21] RP VARIANT GLY-53. RX PubMed=8772735; DOI=10.2337/diab.45.9.1279; RA Sakagashira S., Sanke T., Hanabusa T., Shimomura H., Ohagi S., RA Kumagaye K.Y., Nakajima K., Nanjo K.; RT "Missense mutation of amylin gene (S20G) in Japanese NIDDM patients."; RL Diabetes 45:1279-1281(1996). RN [22] RP VARIANT GLY-53. RX PubMed=9794116; DOI=10.1007/s001250051060; RA Chuang L.M., Lee K.C., Huang C.N., Wu H.P., Tai T.Y., Lin B.J.; RT "Role of S20G mutation of amylin gene in insulin secretion, insulin RT sensitivity, and type II diabetes mellitus in Taiwanese patients."; RL Diabetologia 41:1250-1251(1998). CC -!- FUNCTION: Selectively inhibits insulin-stimulated glucose CC utilization and glycogen deposition in muscle, while not affecting CC adipocyte glucose metabolism. CC -!- SUBUNIT: Interacts with IDE and INS. Can form homodimers. CC Interaction with INS inhibits homodimerization and fibril CC formation. {ECO:0000269|PubMed:17051221, CC ECO:0000269|PubMed:19475663}. CC -!- INTERACTION: CC Self; NbExp=7; IntAct=EBI-8526679, EBI-8526679; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:17374526}. CC -!- DOMAIN: The mature protein is largely unstructured in the absence CC of a cognate ligand, and has a strong tendency to form fibrillar CC aggregates. Homodimerization may be the first step of amyloid CC formation. {ECO:0000269|PubMed:17374526, CC ECO:0000269|PubMed:19244249, ECO:0000269|PubMed:19475663}. CC -!- PTM: Amyloid fibrils are degraded by IDE. CC -!- MASS SPECTROMETRY: Mass=3936; Method=MALDI; Range=34-70; CC Evidence={ECO:0000269|PubMed:17374526}; CC -!- MISCELLANEOUS: IAPP is the peptide subunit of amyloid found in CC pancreatic islets of type 2 diabetic patients and in insulinomas. CC -!- SIMILARITY: Belongs to the calcitonin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Amylin entry; CC URL="https://en.wikipedia.org/wiki/Amylin"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M27503; AAA35524.1; -; Genomic_DNA. DR EMBL; X14904; CAA33032.1; -; mRNA. DR EMBL; X14905; CAA33033.1; -; mRNA. DR EMBL; X14902; CAA33031.1; -; Genomic_DNA. DR EMBL; X14903; CAB57804.1; -; Genomic_DNA. DR EMBL; X13859; CAB57803.1; -; Genomic_DNA. DR EMBL; J04422; AAA52281.1; -; mRNA. DR EMBL; M21785; AAA51728.1; -; Genomic_DNA. DR EMBL; M26650; AAA35983.1; -; Genomic_DNA. DR EMBL; X52818; CAA37002.1; -; Genomic_DNA. DR EMBL; X52819; CAA37002.1; JOINED; Genomic_DNA. DR EMBL; X56030; CAA39504.1; -; Genomic_DNA. DR EMBL; X55634; CAA39504.1; JOINED; Genomic_DNA. DR EMBL; X68830; CAA48724.1; -; Genomic_DNA. DR EMBL; DQ516082; ABG27010.1; -; mRNA. DR EMBL; CH471094; EAW96426.1; -; Genomic_DNA. DR CCDS; CCDS8688.1; -. DR PIR; S04016; TCHUIA. DR RefSeq; NP_000406.1; NM_000415.2. DR UniGene; Hs.46835; -. DR PDB; 1KUW; NMR; -; A=53-62. DR PDB; 2G48; X-ray; 2.60 A; C/D=34-70. DR PDB; 2KB8; NMR; -; A=34-70. DR PDB; 2L86; NMR; -; A=34-70. DR PDB; 3DG1; X-ray; 1.66 A; A=61-66. DR PDB; 3FPO; X-ray; 1.50 A; A=51-56. DR PDB; 3FR1; X-ray; 1.85 A; A=47-52. DR PDB; 3FTH; X-ray; 1.84 A; A/B=47-53. DR PDB; 3FTK; X-ray; 1.50 A; A=64-70. DR PDB; 3FTL; X-ray; 1.60 A; A/B=64-70. DR PDB; 3FTR; X-ray; 1.61 A; A=61-66. DR PDB; 3G7V; X-ray; 1.86 A; A/B/C/D=34-69. DR PDB; 3G7W; X-ray; 1.75 A; A=34-55. DR PDB; 3HGZ; X-ray; 2.91 A; D/E=34-70. DR PDBsum; 1KUW; -. DR PDBsum; 2G48; -. DR PDBsum; 2KB8; -. DR PDBsum; 2L86; -. DR PDBsum; 3DG1; -. DR PDBsum; 3FPO; -. DR PDBsum; 3FR1; -. DR PDBsum; 3FTH; -. DR PDBsum; 3FTK; -. DR PDBsum; 3FTL; -. DR PDBsum; 3FTR; -. DR PDBsum; 3G7V; -. DR PDBsum; 3G7W; -. DR PDBsum; 3HGZ; -. DR ProteinModelPortal; P10997; -. DR SMR; P10997; 34-70. DR DIP; DIP-29913N; -. DR MINT; MINT-8074874; -. DR STRING; 9606.ENSP00000240652; -. DR ChEMBL; CHEMBL1914266; -. DR PhosphoSite; P10997; -. DR BioMuta; IAPP; -. DR DMDM; 124006; -. DR PaxDb; P10997; -. DR PRIDE; P10997; -. DR DNASU; 3375; -. DR Ensembl; ENST00000240652; ENSP00000240652; ENSG00000121351. DR Ensembl; ENST00000539393; ENSP00000437357; ENSG00000121351. DR GeneID; 3375; -. DR KEGG; hsa:3375; -. DR UCSC; uc001rev.3; human. DR CTD; 3375; -. DR GeneCards; IAPP; -. DR HGNC; HGNC:5329; IAPP. DR HPA; CAB000352; -. DR HPA; HPA053194; -. DR MIM; 147940; gene. DR neXtProt; NX_P10997; -. DR PharmGKB; PA29579; -. DR eggNOG; ENOG410J0NB; Eukaryota. DR eggNOG; ENOG410Z7V7; LUCA. DR GeneTree; ENSGT00510000048671; -. DR HOGENOM; HOG000038203; -. DR HOVERGEN; HBG096065; -. DR InParanoid; P10997; -. DR KO; K08039; -. DR OMA; SHQMEKR; -. DR OrthoDB; EOG7TMZVK; -. DR PhylomeDB; P10997; -. DR TreeFam; TF330783; -. DR Reactome; R-HSA-210745; Regulation of gene expression in beta cells. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR Reactome; R-HSA-419812; Calcitonin-like ligand receptors. DR Reactome; R-HSA-977225; Amyloid formation. DR EvolutionaryTrace; P10997; -. DR GeneWiki; Amylin; -. DR GenomeRNAi; 3375; -. DR NextBio; 13352; -. DR PMAP-CutDB; P10997; -. DR PRO; PR:P10997; -. DR Proteomes; UP000005640; Chromosome 12. DR Bgee; P10997; -. DR CleanEx; HS_IAPP; -. DR ExpressionAtlas; P10997; baseline and differential. DR Genevisible; P10997; HS. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0005102; F:receptor binding; TAS:ProtInc. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0031018; P:endocrine pancreas development; TAS:Reactome. DR GO; GO:0045779; P:negative regulation of bone resorption; IEA:Ensembl. DR GO; GO:0045596; P:negative regulation of cell differentiation; IEA:Ensembl. DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR InterPro; IPR021117; Calcitonin-like. DR InterPro; IPR021116; Calcitonin/adrenomedullin. DR InterPro; IPR018360; Calcitonin_CS. DR InterPro; IPR001693; Calcitonin_peptide-like. DR InterPro; IPR000443; Pro-islet_amyloid_polypep. DR PANTHER; PTHR10505; PTHR10505; 1. DR Pfam; PF00214; Calc_CGRP_IAPP; 1. DR PRINTS; PR00818; ISLETAMYLOID. DR SMART; SM00113; CALCITONIN; 1. DR PROSITE; PS00258; CALCITONIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Amidation; Amyloid; Cleavage on pair of basic residues; KW Complete proteome; Direct protein sequencing; Disulfide bond; Hormone; KW Polymorphism; Reference proteome; Secreted; Signal. FT SIGNAL 1 22 {ECO:0000255}. FT PROPEP 23 31 FT /FTId=PRO_0000004105. FT PEPTIDE 34 70 Islet amyloid polypeptide. FT /FTId=PRO_0000004106. FT PROPEP 74 89 FT /FTId=PRO_0000004107. FT MOD_RES 70 70 Tyrosine amide. FT {ECO:0000269|PubMed:2651160, FT ECO:0000269|PubMed:3053705}. FT DISULFID 35 40 {ECO:0000269|PubMed:19244249, FT ECO:0000269|PubMed:19475663, FT ECO:0000269|PubMed:3317417}. FT VARIANT 53 53 S -> G (in dbSNP:rs1800203). FT {ECO:0000269|PubMed:8772735, FT ECO:0000269|PubMed:9794116}. FT /FTId=VAR_012080. FT MUTAGEN 48 48 F->A,D,S: Promotes formation of fibrillar FT aggregates. FT {ECO:0000269|PubMed:19475663}. FT CONFLICT 53 53 S -> C (in Ref. 4; CAA39504). FT {ECO:0000305}. FT HELIX 36 38 {ECO:0000244|PDB:2G48}. FT HELIX 43 49 {ECO:0000244|PDB:3G7W}. FT HELIX 53 60 {ECO:0000244|PDB:3G7V}. FT TURN 63 69 {ECO:0000244|PDB:2L86}. SQ SEQUENCE 89 AA; 9806 MW; AA8B1F7FD9FCB4BD CRC64; MGILKLQVFL IVLSVALNHL KATPIESHQV EKRKCNTATC ATQRLANFLV HSSNNFGAIL SSTNVGSNTY GKRNAVEVLK REPLNYLPL //