ID   EXE2_HELSU              Reviewed;          84 AA.
AC   P04204;
DT   20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
DT   14-DEC-2011, sequence version 3.
DT   25-MAY-2022, entry version 78.
DE   RecName: Full=Exendin-2-long;
DE   Contains:
DE     RecName: Full=Exendin-2;
DE     AltName: Full=Helodermin;
DE     AltName: Full=VIP-like 2;
DE   Flags: Precursor;
OS   Heloderma suspectum (Gila monster).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC   Anguimorpha; Neoanguimorpha; Helodermatidae; Heloderma.
OX   NCBI_TaxID=8554;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX   PubMed=9545315; DOI=10.1074/jbc.273.16.9778;
RA   Pohl M., Wank S.A.;
RT   "Molecular cloning of the helodermin and exendin-4 cDNAs in the lizard.
RT   Relationship to vasoactive intestinal polypeptide/pituitary adenylate
RT   cyclase activating polypeptide and glucagon-like peptide 1 and evidence
RT   against the existence of mammalian homologues.";
RL   J. Biol. Chem. 273:9778-9784(1998).
RN   [2]
RP   PROTEIN SEQUENCE OF 47-81.
RC   TISSUE=Venom;
RX   PubMed=6439576; DOI=10.1016/0014-5793(84)80607-9;
RA   Hoshino M., Yanaihara C., Hong Y.M., Kishida S., Katsumaru Y.,
RA   Vandermeers A., Vandermeers-Piret M.-C., Robberecht P., Christophe J.,
RA   Yanaihara N.;
RT   "Primary structure of helodermin, a VIP-secretin-like peptide isolated from
RT   Gila monster venom.";
RL   FEBS Lett. 178:233-239(1984).
RN   [3]
RP   SEQUENCE REVISION TO 54-55.
RX   PubMed=3569266; DOI=10.1111/j.1432-1033.1987.tb11061.x;
RA   Vandermeers A., Gourlet P., Vandermeers-Piret M.C., Cauvin A., De Neef P.,
RA   Rathe J., Svoboda M., Robberecht P., Christophe J.;
RT   "Chemical, immunological and biological properties of peptides like
RT   vasoactive-intestinal-peptide and peptide-histidine-isoleucinamide
RT   extracted from the venom of two lizards (Heloderma horridum and Heloderma
RT   suspectum).";
RL   Eur. J. Biochem. 164:321-327(1987).
RN   [4]
RP   SEQUENCE REVISION TO 82-83.
RX   PubMed=10880980; DOI=10.1046/j.1432-1327.2000.01506.x;
RA   Vandermeers-Piret M.C., Vandermeers A., Gourlet P., Ali M.H.,
RA   Waelbroeck M., Robberecht P.;
RT   "Evidence that the lizard helospectin peptides are O-glycosylated.";
RL   Eur. J. Biochem. 267:4556-4560(2000).
RN   [5]
RP   FUNCTION.
RX   PubMed=9928018; DOI=10.1111/j.1749-6632.1998.tb11184.x;
RA   Gourlet P., Vandermeers A., Van Rampelbergh J., De Neef P., Cnudde J.,
RA   Waelbroeck M., Robberecht P.;
RT   "Analogues of VIP, helodermin, and PACAP discriminate between rat and human
RT   VIP1 and VIP2 receptors.";
RL   Ann. N. Y. Acad. Sci. 865:247-252(1998).
RN   [6]
RP   FUNCTION.
RX   PubMed=15003357; DOI=10.1016/j.peptides.2003.11.010;
RA   Tsueshita T., Onyukusel H., Sethi V., Gandhi S., Rubinstein I.;
RT   "Helospectin I and II evoke vasodilation in the intact peripheral
RT   microcirculation.";
RL   Peptides 25:65-69(2004).
RN   [7]
RP   SYNTHESIS, AND FUNCTION.
RX   PubMed=19837656; DOI=10.1093/molbev/msp251;
RA   Fry B.G., Roelants K., Winter K., Hodgson W.C., Griesman L., Kwok H.F.,
RA   Scanlon D., Karas J., Shaw C., Wong L., Norman J.A.;
RT   "Novel venom proteins produced by differential domain-expression strategies
RT   in beaded lizards and gila monsters (genus Heloderma).";
RL   Mol. Biol. Evol. 27:395-407(2010).
RN   [8]
RP   STRUCTURE BY NMR OF 47-81, AND SYNTHESIS OF 47-81 (AMIDATED).
RX   PubMed=8634236; DOI=10.1021/bi9601520;
RA   Blankenfekdt W., Nokihara K., Naruse S., Lessel U., Schomburg D., Wray V.;
RT   "NMR spectroscopic evidence that helodermin, unlike other members of the
RT   secretin/VIP family of peptides, is substantially structured in water.";
RL   Biochemistry 35:5955-5962(1996).
CC   -!- FUNCTION: Has vasoactive intestinal peptide(VIP)/secretin-like
CC       biological activity. Interacts with rat and human VIP receptors 1
CC       (VIPR1) and 2 (VIPR2), with the highest affinity for the human VIPR2.
CC       Induces hypotension that is mediated by relaxation of cardiac smooth
CC       muscle. This vasodilation may not be transduced by VIP or PACAP
CC       receptors. {ECO:0000269|PubMed:15003357, ECO:0000269|PubMed:19837656,
CC       ECO:0000269|PubMed:9928018}.
CC   -!- SUBCELLULAR LOCATION: Secreted.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland. Not expressed in the
CC       pancreas, liver, stomach, small intestine, lung, heart, kidney, spleen,
CC       ovary, and brain. {ECO:0000269|PubMed:9545315}.
CC   -!- PTM: An amidated Pro-81 is described (PubMed:6439576, PubMed:3569266).
CC       Such an amidation is however not compatible with the sequence displayed
CC       (PubMed:9545315 and PubMed:10880980). Indeed cDNAs do not encode a Gly
CC       that could serve as substrate for peptide alpha-amidation.
CC       {ECO:0000269|PubMed:3569266, ECO:0000269|PubMed:6439576}.
CC   -!- SIMILARITY: Belongs to the glucagon family. {ECO:0000305}.
CC   -!- CAUTION: A longer peptide than exendin-2 has been described in the
CC       venom (PubMed:10880980). It has been indicated here as exendin-2-long.
CC       {ECO:0000305|PubMed:10880980}.
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DR   PIR; A01556; HWGHD.
DR   AlphaFoldDB; P04204; -.
DR   SMR; P04204; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005179; F:hormone activity; IEA:InterPro.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR   GO; GO:0008217; P:regulation of blood pressure; IEA:UniProtKB-KW.
DR   InterPro; IPR000532; Glucagon_GIP_secretin_VIP.
DR   Pfam; PF00123; Hormone_2; 1.
DR   SMART; SM00070; GLUCA; 1.
DR   PROSITE; PS00260; GLUCAGON; 1.
PE   1: Evidence at protein level;
KW   Cleavage on pair of basic residues; Direct protein sequencing;
KW   G-protein coupled receptor impairing toxin; Hypotensive agent; Secreted;
KW   Signal; Toxin.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000255"
FT   PROPEP          24..44
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000414094"
FT   PEPTIDE         47..83
FT                   /note="Exendin-2-long"
FT                   /id="PRO_0000414095"
FT   PEPTIDE         47..81
FT                   /note="Exendin-2"
FT                   /id="PRO_0000044747"
SQ   SEQUENCE   84 AA;  9531 MW;  4CC1F9B3177897FD CRC64;
     MKSILWLCVF GLLIATLFPV SWQMAIKSRL SSEDSETDQR LFESKRHSDA IFTEEYSKLL
     AKLALQKYLA SILGSRTSPP PPSR