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 27-MAR-2024, entry version 198. 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; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC 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., Miyata A., RA Arimura A., Fujino M.; RT "Primary structure and characterization of the precursor to human pituitary RT 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., Shimizu M., RA Onda H., Oshimura M., Arimura A., Fujino M.; RT "Structure of the human pituitary adenylate cyclase activating polypeptide RT (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., 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 [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 project: RT 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 and RT 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 Neuronal RT 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 polypeptide RT 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., Ogi K., RA 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 OF RP 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 cyclase- RT activating polypeptide binding to the extracellular domain of 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 2 RT diabetes."; RL Hum. Mutat. 19:572-573(2002). CC -!- FUNCTION: Binding to its receptor activates G proteins and stimulates CC adenylate cyclase in pituitary cells. Promotes neuron projection CC development through the RAPGEF2/Rap1/B-Raf/ERK pathway. In chromaffin CC cells, induces long-lasting increase of intracellular calcium CC concentrations and neuroendocrine secretion (By similarity). Involved CC in the control of glucose homeostasis, induces insulin secretion by CC pancreatic beta cells (By similarity). {ECO:0000250|UniProtKB:O70176, CC ECO:0000250|UniProtKB:P13589, ECO:0000269|PubMed:11175907, CC ECO:0000269|PubMed:23800469}. CC -!- SUBUNIT: Interacts with ADCYAP1R1 (via N-terminal extracellular CC domain). {ECO:0000269|PubMed:17470806}. CC -!- INTERACTION: CC P18509; P41586-3: ADCYAP1R1; NbExp=2; IntAct=EBI-8588930, EBI-15635217; CC P18509; P05067: APP; NbExp=3; IntAct=EBI-8588930, EBI-77613; CC P18509; 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 PDB; 1GEA; NMR; -; A=132-152. DR PDB; 2D2P; NMR; -; A=132-169. DR PDB; 2JOD; NMR; -; B=137-169. DR PDB; 6LPB; EM; 3.90 A; P=132-169. DR PDB; 6M1I; EM; 3.50 A; B=132-169. DR PDB; 6P9Y; EM; 3.01 A; P=132-169. DR PDB; 6VN7; EM; 3.20 A; L=132-158. DR PDB; 7VQX; EM; 2.74 A; L=132-158. DR PDB; 7WBJ; EM; 3.42 A; L=132-158. DR PDB; 8E3X; EM; 2.30 A; P=132-158. DR PDB; 8E3Y; EM; 2.30 A; P=132-158. DR PDBsum; 1GEA; -. DR PDBsum; 2D2P; -. DR PDBsum; 2JOD; -. DR PDBsum; 6LPB; -. DR PDBsum; 6M1I; -. DR PDBsum; 6P9Y; -. DR PDBsum; 6VN7; -. DR PDBsum; 7VQX; -. DR PDBsum; 7WBJ; -. DR PDBsum; 8E3X; -. DR PDBsum; 8E3Y; -. DR AlphaFoldDB; P18509; -. DR BMRB; P18509; -. DR EMDB; EMD-0940; -. DR EMDB; EMD-20278; -. DR EMDB; EMD-21249; -. DR EMDB; EMD-30048; -. DR EMDB; EMD-32095; -. DR EMDB; EMD-32401; -. DR SMR; P18509; -. DR BioGRID; 106629; 35. DR DIP; DIP-60936N; -. DR IntAct; P18509; 23. DR MINT; P18509; -. DR STRING; 9606.ENSP00000462647; -. DR BindingDB; P18509; -. DR DrugBank; DB03988; 2,6-Diamino-Hexanoic Acid Amide. DR iPTMnet; P18509; -. DR PhosphoSitePlus; P18509; -. DR BioMuta; ADCYAP1; -. DR DMDM; 71159615; -. DR MassIVE; P18509; -. DR PaxDb; 9606-ENSP00000462647; -. DR PeptideAtlas; P18509; -. DR ProteomicsDB; 53571; -. DR ABCD; P18509; 29 sequenced antibodies. DR Antibodypedia; 41707; 405 antibodies from 31 providers. DR DNASU; 116; -. DR Ensembl; ENST00000450565.8; ENSP00000411658.3; ENSG00000141433.13. DR Ensembl; ENST00000579794.1; ENSP00000462647.1; ENSG00000141433.13. DR GeneID; 116; -. DR KEGG; hsa:116; -. DR MANE-Select; ENST00000450565.8; ENSP00000411658.3; NM_001099733.2; NP_001093203.1. DR UCSC; uc010dkg.4; human. DR AGR; HGNC:241; -. DR CTD; 116; -. DR DisGeNET; 116; -. DR GeneCards; ADCYAP1; -. DR HGNC; HGNC:241; ADCYAP1. DR HPA; ENSG00000141433; Tissue enhanced (brain, lymphoid tissue). DR MIM; 102980; gene. DR neXtProt; NX_P18509; -. DR OpenTargets; ENSG00000141433; -. DR PharmGKB; PA24564; -. DR VEuPathDB; HostDB:ENSG00000141433; -. DR eggNOG; ENOG502QSGB; Eukaryota. DR GeneTree; ENSGT00950000183154; -. DR HOGENOM; CLU_118633_0_0_1; -. DR InParanoid; P18509; -. DR OMA; LYGIIMH; -. DR OrthoDB; 3925933at2759; -. DR PhylomeDB; P18509; -. DR TreeFam; TF332804; -. DR PathwayCommons; P18509; -. 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 SignaLink; P18509; -. DR SIGNOR; P18509; -. DR BioGRID-ORCS; 116; 10 hits in 1141 CRISPR screens. DR EvolutionaryTrace; P18509; -. DR GeneWiki; Pituitary_adenylate_cyclase-activating_peptide; -. DR GenomeRNAi; 116; -. DR Pharos; P18509; Tbio. DR PRO; PR:P18509; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P18509; Protein. DR Bgee; ENSG00000141433; Expressed in type B pancreatic cell and 119 other cell types or tissues. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0043204; C:perikaryon; IBA:GO_Central. 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:signaling receptor binding; IPI:BHF-UCL. DR GO; GO:0007190; P:activation of adenylate cyclase activity; TAS:ProtInc. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL. 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:0030073; P:insulin secretion; ISS:UniProtKB. 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:0071651; P:positive regulation of chemokine (C-C motif) ligand 5 production; IDA:CACAO. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0060124; P:positive regulation of growth hormone secretion; ISS: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 by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0032880; P:regulation of protein localization; IDA:BHF-UCL. DR Gene3D; 6.10.250.590; -; 1. DR InterPro; IPR000532; Glucagon_GIP_secretin_VIP. DR InterPro; IPR046963; VIP/GHRH-like. DR PANTHER; PTHR11213; GLUCAGON-FAMILY NEUROPEPTIDE; 1. DR PANTHER; PTHR11213:SF1; PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE; 1. DR Pfam; PF00123; Hormone_2; 2. DR PRINTS; PR00275; GLUCAGON. DR SMART; SM00070; GLUCA; 2. DR PROSITE; PS00260; GLUCAGON; 1. DR Genevisible; P18509; HS. PE 1: Evidence at protein level; KW 3D-structure; Amidation; Cleavage on pair of basic residues; Hormone; KW Neurogenesis; Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT PROPEP 25..79 FT /id="PRO_0000011486" FT PEPTIDE 82..129 FT /note="PACAP-related peptide" FT /id="PRO_0000011487" FT PEPTIDE 132..169 FT /note="Pituitary adenylate cyclase-activating polypeptide FT 38" FT /id="PRO_0000011488" FT PEPTIDE 132..158 FT /note="Pituitary adenylate cyclase-activating polypeptide FT 27" FT /id="PRO_0000011489" FT PROPEP 173..176 FT /id="PRO_0000011490" FT REGION 39..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 150..158 FT /note="Important for receptor binding" FT MOD_RES 158 FT /note="Leucine amide" FT /evidence="ECO:0000269|PubMed:2302217" FT MOD_RES 169 FT /note="Lysine amide" FT /evidence="ECO:0000269|PubMed:2302217" FT VARIANT 54 FT /note="D -> G (in dbSNP:rs2856966)" FT /evidence="ECO:0000269|PubMed:11968092, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:1730060, FT ECO:0000269|PubMed:1739432" FT /id="VAR_014597" FT MUTAGEN 150 FT /note="V->G: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT MUTAGEN 151 FT /note="K->E: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT MUTAGEN 152 FT /note="K->E: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT MUTAGEN 153 FT /note="Y->A: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT MUTAGEN 157 FT /note="V->A: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT MUTAGEN 158 FT /note="L->A: Strongly reduced affinity for ADCYAP1R1." FT /evidence="ECO:0000269|PubMed:17470806" FT HELIX 133..157 FT /evidence="ECO:0007829|PDB:7VQX" 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 //