PACA_HUMAN
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 03-AUG-2022, entry version 189.
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}.
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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 PDBsum; 1GEA; -.
DR PDBsum; 2D2P; -.
DR PDBsum; 2JOD; -.
DR PDBsum; 6LPB; -.
DR PDBsum; 6M1I; -.
DR PDBsum; 6P9Y; -.
DR PDBsum; 6VN7; -.
DR AlphaFoldDB; P18509; -.
DR BMRB; P18509; -.
DR SMR; P18509; -.
DR BioGRID; 106629; 34.
DR DIP; DIP-60936N; -.
DR IntAct; P18509; 22.
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; P18509; -.
DR PeptideAtlas; P18509; -.
DR PRIDE; P18509; -.
DR ProteomicsDB; 53571; -.
DR ABCD; P18509; 29 sequenced antibodies.
DR Antibodypedia; 41707; 287 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 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; QDFAYDQ; -.
DR OrthoDB; 1146285at2759; -.
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 Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR SABIO-RK; P18509; -.
DR SignaLink; P18509; -.
DR SIGNOR; P18509; -.
DR BioGRID-ORCS; 116; 9 hits in 1065 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 118 other tissues.
DR Genevisible; P18509; HS.
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:0031858; F:pituitary adenylate cyclase-activating polypeptide receptor binding; IEA:InterPro.
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 InterPro; IPR015550; Glucagon.
DR InterPro; IPR000532; Glucagon_GIP_secretin_VIP.
DR InterPro; IPR039080; PACAP.
DR PANTHER; PTHR11213; PTHR11213; 1.
DR PANTHER; PTHR11213:SF1; PTHR11213:SF1; 1.
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; 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 134..157
FT /evidence="ECO:0007829|PDB:6P9Y"
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
