ID PACA_HUMAN Reviewed; 176 AA. AC P18509; B2R7N4; Q52LQ0; DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot. DT 10-MAY-2005, sequence version 3. DT 11-NOV-2015, entry version 142. DE RecName: Full=Pituitary adenylate cyclase-activating polypeptide; DE Short=PACAP; DE Contains: DE RecName: Full=PACAP-related peptide; DE AltName: Full=PRP-48; DE Contains: DE RecName: Full=Pituitary adenylate cyclase-activating polypeptide 27; DE Short=PACAP-27; DE Short=PACAP27; DE Contains: DE RecName: Full=Pituitary adenylate cyclase-activating polypeptide 38; DE Short=PACAP-38; DE Short=PACAP38; DE Flags: Precursor; GN Name=ADCYAP1; 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 [MRNA], AND VARIANT GLY-54. RC TISSUE=Testis; RX PubMed=1739432; DOI=10.1089/dna.1992.11.21; RA Ohkubo S., Kimura C., Ogi K., Okazaki K., Hosoya M., Onda H., RA Miyata A., Arimura A., Fujino M.; RT "Primary structure and characterization of the precursor to human RT pituitary adenylate cyclase activating polypeptide."; RL DNA Cell Biol. 11:21-30(1992). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-54. RX PubMed=1730060; DOI=10.1016/0167-4781(92)90488-L; RA Hosoya M., Kimura C., Ogi K., Ohkubo S., Miyamoto Y., Kugoh H., RA Shimizu M., Onda H., Oshimura M., Arimura A., Fujino M.; RT "Structure of the human pituitary adenylate cyclase activating RT polypeptide (PACAP) gene."; RL Biochim. Biophys. Acta 1129:199-206(1992). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-54. RC TISSUE=Brain; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 114-176, AND AMIDATION AT LEU-158 AND RP LYS-169. RX PubMed=2302217; DOI=10.1016/0006-291X(90)91914-E; RA Kimura C., Ohkubo S., Ogi K., Hosoya M., Itoh Y., Onda H., Miyata A., RA Jiang L., Dahl R.R., Stibbs H.H., Arimura A., Fujino M.; RT "A novel peptide which stimulates adenylate cyclase: molecular cloning RT and characterization of the ovine and human cDNAs."; RL Biochem. Biophys. Res. Commun. 166:81-89(1990). RN [6] RP FUNCTION. RX PubMed=23800469; DOI=10.1126/scisignal.2003993; RA Emery A.C., Eiden M.V., Mustafa T., Eiden L.E.; RT "Rapgef2 Connects GPCR-Mediated cAMP Signals to ERK Activation in RT Neuronal and Endocrine Cells."; RL Sci. Signal. 6:RA51-RA51(2013). RN [7] RP STRUCTURE BY NMR OF 132-169. RX PubMed=8504103; DOI=10.1021/bi00073a016; RA Wray V., Kakoschke C., Nokihara K., Naruse S.; RT "Solution structure of pituitary adenylate cyclase activating RT polypeptide by nuclear magnetic resonance spectroscopy."; RL Biochemistry 32:5832-5841(1993). RN [8] RP STRUCTURE BY NMR OF 132-158. RX PubMed=1483839; RA Inooka H., Endo S., Kitada C., Mizuta E., Fujino M.; RT "Pituitary adenylate cyclase activating polypeptide (PACAP) with 27 RT residues. Conformation determined by 1H NMR and CD spectroscopies and RT distance geometry in 25% methanol solution."; RL Int. J. Pept. Protein Res. 40:456-464(1992). RN [9] RP STRUCTURE BY NMR OF 132-152, AND FUNCTION. RX PubMed=11175907; DOI=10.1038/84159; RA Inooka H., Ohtaki T., Kitahara O., Ikegami T., Endo S., Kitada C., RA Ogi K., Onda H., Fujino M., Shirakawa M.; RT "Conformation of a peptide ligand bound to its G-protein coupled RT receptor."; RL Nat. Struct. Biol. 8:161-165(2001). RN [10] RP STRUCTURE BY NMR OF 137-169 IN COMPLEX WITH ADCYAP1R1, AND MUTAGENESIS RP OF VAL-150; LYS-151; LYS-152; TYR-153; VAL-157 AND LEU-158. RX PubMed=17470806; DOI=10.1073/pnas.0611397104; RA Sun C., Song D., Davis-Taber R.A., Barrett L.W., Scott V.E., RA Richardson P.L., Pereda-Lopez A., Uchic M.E., Solomon L.R., Lake M.R., RA Walter K.A., Hajduk P.J., Olejniczak E.T.; RT "Solution structure and mutational analysis of pituitary adenylate RT cyclase-activating polypeptide binding to the extracellular domain of RT PAC1-RS."; RL Proc. Natl. Acad. Sci. U.S.A. 104:7875-7880(2007). RN [11] RP VARIANT GLY-54. RX PubMed=11968092; DOI=10.1002/humu.9034; RA Gu H.F.; RT "Genetic variation screening and association studies of the adenylate RT cyclase activating polypeptide 1 (ADCYAP1) gene in patients with type RT 2 diabetes."; RL Hum. Mutat. 19:572-573(2002). CC -!- FUNCTION: Binding to its receptor activates G proteins and CC stimulates adenylate cyclase in pituitary cells. Promotes neuron CC projection development through the RAPGEF2/Rap1/B-Raf/ERK pathway. CC {ECO:0000269|PubMed:11175907, ECO:0000269|PubMed:23800469}. CC -!- SUBUNIT: Interacts with ADCYAP1R1 (via N-terminal extracellular CC domain). {ECO:0000269|PubMed:17470806}. CC -!- INTERACTION: CC P10909:CLU; NbExp=4; IntAct=EBI-8588930, EBI-1104674; CC -!- SUBCELLULAR LOCATION: Secreted. CC -!- SIMILARITY: Belongs to the glucagon family. {ECO:0000305}. 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; S83513; AAB21470.1; -; mRNA. DR EMBL; X60435; CAA42962.1; -; Genomic_DNA. DR EMBL; AK313050; BAG35881.1; -; mRNA. DR EMBL; BC093837; AAH93837.1; -; mRNA. DR EMBL; BC101803; AAI01804.1; -; mRNA. DR CCDS; CCDS11825.1; -. DR PIR; I84638; I84638. DR RefSeq; NP_001093203.1; NM_001099733.1. DR RefSeq; NP_001108.2; NM_001117.4. DR UniGene; Hs.531719; -. DR UniGene; Hs.727476; -. DR PDB; 1GEA; NMR; -; A=132-152. DR PDB; 2D2P; NMR; -; A=132-169. DR PDB; 2JOD; NMR; -; B=137-169. DR PDBsum; 1GEA; -. DR PDBsum; 2D2P; -. DR PDBsum; 2JOD; -. DR ProteinModelPortal; P18509; -. DR SMR; P18509; 85-110, 132-169. DR BioGrid; 106629; 26. DR DIP; DIP-60936N; -. DR IntAct; P18509; 3. DR MINT; MINT-2801501; -. DR STRING; 9606.ENSP00000411658; -. DR BindingDB; P18509; -. DR ChEMBL; CHEMBL5692; -. DR PhosphoSite; P18509; -. DR BioMuta; ADCYAP1; -. DR DMDM; 71159615; -. DR PaxDb; P18509; -. DR PRIDE; P18509; -. DR DNASU; 116; -. DR Ensembl; ENST00000450565; ENSP00000411658; ENSG00000141433. DR Ensembl; ENST00000579794; ENSP00000462647; ENSG00000141433. DR GeneID; 116; -. DR KEGG; hsa:116; -. DR UCSC; uc010dkg.3; human. DR CTD; 116; -. DR GeneCards; ADCYAP1; -. DR HGNC; HGNC:241; ADCYAP1. DR MIM; 102980; gene. DR neXtProt; NX_P18509; -. DR PharmGKB; PA24564; -. DR eggNOG; ENOG410IWIZ; Eukaryota. DR eggNOG; ENOG4111FZG; LUCA. DR GeneTree; ENSGT00530000063592; -. DR HOVERGEN; HBG018069; -. DR InParanoid; P18509; -. DR KO; K05262; -. DR OMA; RYRQRIR; -. DR OrthoDB; EOG7M6D8P; -. DR PhylomeDB; P18509; -. DR TreeFam; TF332804; -. DR Reactome; R-HSA-187024; NGF-independant TRKA activation. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR Reactome; R-HSA-420092; Glucagon-type ligand receptors. DR SABIO-RK; P18509; -. DR EvolutionaryTrace; P18509; -. DR GeneWiki; Pituitary_adenylate_cyclase-activating_peptide; -. DR GenomeRNAi; 116; -. DR NextBio; 449; -. DR PRO; PR:P18509; -. DR Proteomes; UP000005640; Chromosome 18. DR Bgee; P18509; -. DR CleanEx; HS_ADCYAP1; -. DR Genevisible; P18509; HS. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005622; C:intracellular; IMP:GOC. DR GO; GO:0005184; F:neuropeptide hormone activity; IDA:UniProtKB. DR GO; GO:0051428; F:peptide hormone receptor binding; IDA:UniProtKB. DR GO; GO:0016521; F:pituitary adenylate cyclase activating polypeptide activity; IDA:BHF-UCL. DR GO; GO:0005102; F:receptor binding; IPI:BHF-UCL. DR GO; GO:0005057; F:receptor signaling protein activity; IEA:Ensembl. DR GO; GO:0007190; P:activation of adenylate cyclase activity; TAS:Reactome. DR GO; GO:0019933; P:cAMP-mediated signaling; IMP:UniProtKB. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0007565; P:female pregnancy; TAS:ProtInc. DR GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl. DR GO; GO:0031175; P:neuron projection development; IDA:UniProtKB. DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome. DR GO; GO:0010579; P:positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0071651; P:positive regulation of chemokine (C-C motif) ligand 5 production; IDA:CACAO. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; IDA:UniProtKB. DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB. DR GO; GO:0008277; P:regulation of G-protein coupled receptor protein signaling pathway; IDA:UniProtKB. DR GO; GO:0032880; P:regulation of protein localization; IDA:BHF-UCL. DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; TAS:Reactome. DR InterPro; IPR000532; Glucagon_GIP_secretin_VIP. DR Pfam; PF00123; Hormone_2; 2. DR PRINTS; PR00275; GLUCAGON. DR SMART; SM00070; GLUCA; 2. DR PROSITE; PS00260; GLUCAGON; 1. PE 1: Evidence at protein level; KW 3D-structure; Amidation; Cleavage on pair of basic residues; KW Complete proteome; Hormone; Neurogenesis; Polymorphism; KW Reference proteome; Secreted; Signal. FT SIGNAL 1 24 {ECO:0000255}. FT PROPEP 25 79 FT /FTId=PRO_0000011486. FT PEPTIDE 82 129 PACAP-related peptide. FT /FTId=PRO_0000011487. FT PEPTIDE 132 169 Pituitary adenylate cyclase-activating FT polypeptide 38. FT /FTId=PRO_0000011488. FT PEPTIDE 132 158 Pituitary adenylate cyclase-activating FT polypeptide 27. FT /FTId=PRO_0000011489. FT PROPEP 173 176 FT /FTId=PRO_0000011490. FT REGION 150 158 Important for receptor binding. FT MOD_RES 158 158 Leucine amide. FT {ECO:0000269|PubMed:2302217}. FT MOD_RES 169 169 Lysine amide. FT {ECO:0000269|PubMed:2302217}. FT VARIANT 54 54 D -> G (in dbSNP:rs2856966). FT {ECO:0000269|PubMed:11968092, FT ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:1730060, FT ECO:0000269|PubMed:1739432}. FT /FTId=VAR_014597. FT MUTAGEN 150 150 V->G: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT MUTAGEN 151 151 K->E: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT MUTAGEN 152 152 K->E: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT MUTAGEN 153 153 Y->A: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT MUTAGEN 157 157 V->A: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT MUTAGEN 158 158 L->A: Strongly reduced affinity for FT ADCYAP1R1. {ECO:0000269|PubMed:17470806}. FT STRAND 135 139 {ECO:0000244|PDB:1GEA}. FT HELIX 140 150 {ECO:0000244|PDB:1GEA}. FT HELIX 153 160 {ECO:0000244|PDB:2JOD}. SQ SEQUENCE 176 AA; 18835 MW; 696DD57D2A510E1D CRC64; MTMCSGARLA LLVYGIIMHS SVYSSPAAAG LRFPGIRPEE EAYGEDGNPL PDFDGSEPPG AGSPASAPRA AAAWYRPAGR RDVAHGILNE AYRKVLDQLS AGKHLQSLVA RGVGGSLGGG AGDDAEPLSK RHSDGIFTDS YSRYRKQMAV KKYLAAVLGK RYKQRVKNKG RRIAYL //