INS1A_CONGE
ID INS1A_CONGE Reviewed; 115 AA.
AC A0A0B5AC95;
DT 15-MAR-2017, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-2015, sequence version 1.
DT 25-MAY-2022, entry version 30.
DE RecName: Full=Con-Ins G1a {ECO:0000303|PubMed:25605914};
DE AltName: Full=Insulin 1 {ECO:0000312|EMBL:AJD85832.1};
DE Contains:
DE RecName: Full=Con-Ins G1 B chain {ECO:0000303|PubMed:25605914};
DE Contains:
DE RecName: Full=Con-Ins G1a A chain {ECO:0000303|PubMed:25605914};
DE Flags: Precursor;
OS Conus geographus (Geography cone) (Nubecula geographus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX NCBI_TaxID=6491;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 30-52 AND 95-114, MASS
RP SPECTROMETRY, HYDROXYLATION AT PRO-34 AND PRO-104, GAMMA-CARBOXYGLUTAMATION
RP AT GLU-41; GLU-98 AND GLU-109, AMIDATION AT CYS-114, SYNTHESIS OF 30-52 AND
RP 95-114, SUBCELLULAR LOCATION, AND BIOASSAY.
RC TISSUE=Venom, and Venom gland;
RX PubMed=25605914; DOI=10.1073/pnas.1423857112;
RA Safavi-Hemami H., Gajewiak J., Karanth S., Robinson S.D., Ueberheide B.,
RA Douglass A.D., Schlegel A., Imperial J.S., Watkins M., Bandyopadhyay P.K.,
RA Yandell M., Li Q., Purcell A.W., Norton R.S., Ellgaard L., Olivera B.M.;
RT "Specialized insulin is used for chemical warfare by fish-hunting cone
RT snails.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:1743-1748(2015).
RN [2]
RP FUNCTION, SYNTHESIS OF 30-52 AND 95-114, AND 3D-STRUCTURE MODELING IN
RP COMPLEX WITH HUMAN INSULIN RECEPTOR.
RX PubMed=30747102; DOI=10.7554/elife.41574;
RA Ahorukomeye P., Disotuar M.M., Gajewiak J., Karanth S., Watkins M.,
RA Robinson S.D., Florez Salcedo P., Smith N.A., Smith B.J., Schlegel A.,
RA Forbes B.E., Olivera B., Hung-Chieh Chou D., Safavi-Hemami H.;
RT "Fish-hunting cone snail venoms are a rich source of minimized ligands of
RT the vertebrate insulin receptor.";
RL Elife 8:0-0(2019).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 30-52 AND 95-114, FUNCTION,
RP DISULFIDE BONDS, SYNTHESIS OF 30-52 AND 95-114, AND SUBUNIT.
RX PubMed=27617429; DOI=10.1038/nsmb.3292;
RA Menting J.G., Gajewiak J., MacRaild C.A., Chou D.H., Disotuar M.M.,
RA Smith N.A., Miller C., Erchegyi J., Rivier J.E., Olivera B.M., Forbes B.E.,
RA Smith B.J., Norton R.S., Safavi-Hemami H., Lawrence M.C.;
RT "A minimized human insulin-receptor-binding motif revealed in a Conus
RT geographus venom insulin.";
RL Nat. Struct. Mol. Biol. 23:916-920(2016).
CC -!- FUNCTION: This venom insulin, from a fish-hunting cone snail,
CC facilitates prey capture by rapidly inducing hypoglycemic shock
CC (PubMed:25605914, PubMed:27617429). It is one of the smallest known
CC insulin found in nature and lacks the C-terminal segment of the B chain
CC that, in human insulin, mediates engagement of the insulin receptor and
CC assembly of the hormone's hexameric storage form (PubMed:27617429).
CC Despite lacking this segment, it both binds and activates human insulin
CC receptor (long isoform (HIR-B)) with a high potency (EC(50)=16.28 nM)
CC (PubMed:30747102, PubMed:27617429). In vivo, intraperitoneal injection
CC of this peptide into zebrafish lowers blood glucose with the same
CC potency than human insulin (PubMed:25605914, PubMed:30747102). In
CC addition, when applied to water, this peptide reduces overall locomotor
CC activity of zebrafish larvae, observed as a significant decrease in the
CC percentage of time spent swimming and movement frequency
CC (PubMed:25605914). When tested on a mouse model of diabetes, this
CC insulin also lowers blood glucose with a 10-fold lower potency than
CC human insulin (PubMed:30747102). {ECO:0000269|PubMed:25605914,
CC ECO:0000269|PubMed:27617429, ECO:0000269|PubMed:30747102}.
CC -!- SUBUNIT: Heterodimer of A and B chains; disulfide-linked.
CC {ECO:0000269|PubMed:27617429}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:25605914}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:25605914}.
CC -!- MASS SPECTROMETRY: Mass=5030.1; Method=Electrospray; Note=with 1
CC hydroxyPro (residue 34) and with 3 carboxyglutamate (residues 41, 98
CC and 109). The measured ranges are 30-52, 95-114.;
CC Evidence={ECO:0000269|PubMed:25605914};
CC -!- MASS SPECTROMETRY: Mass=5046.1; Method=Electrospray; Note=with 2
CC hydroxyPro (residues 34 and 104) and with 3 carboxyglutamate (residues
CC 41, 98 and 109). The measured ranges are 30-52, 95-114.;
CC Evidence={ECO:0000269|PubMed:25605914};
CC -!- MASS SPECTROMETRY: Mass=5014.1; Method=Electrospray; Note=without
CC hydroxyPro and with 3 carboxyglutamate (residues 41, 98 and 109). The
CC measured ranges are 30-52, 95-114.;
CC Evidence={ECO:0000269|PubMed:25605914};
CC -!- MISCELLANEOUS: Venom insulins constitute about 1/25 of the total venom
CC of C.geographus. {ECO:0000305|PubMed:25605914}.
CC -!- SIMILARITY: Belongs to the insulin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Sweet poison - Issue 191 of
CC May 2017;
CC URL="https://web.expasy.org/spotlight/back_issues/191/";
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DR EMBL; KP268599; AJD85832.1; -; mRNA.
DR PDB; 5JYQ; X-ray; 1.95 A; A=95-114, B=30-52.
DR PDB; 6VEQ; X-ray; 3.25 A; A/G=95-114.
DR PDBsum; 5JYQ; -.
DR PDBsum; 6VEQ; -.
DR AlphaFoldDB; A0A0B5AC95; -.
DR SMR; A0A0B5AC95; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005179; F:hormone activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR InterPro; IPR016179; Insulin-like.
DR InterPro; IPR036438; Insulin-like_sf.
DR InterPro; IPR022353; Insulin_CS.
DR InterPro; IPR022352; Insulin_family.
DR Pfam; PF00049; Insulin; 1.
DR PRINTS; PR00276; INSULINFAMLY.
DR SMART; SM00078; IlGF; 1.
DR SUPFAM; SSF56994; SSF56994; 1.
DR PROSITE; PS00262; INSULIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Carbohydrate metabolism;
KW Cleavage on pair of basic residues; Direct protein sequencing;
KW Disulfide bond; Gamma-carboxyglutamic acid; Glucose metabolism; Hormone;
KW Hydroxylation; Secreted; Signal; Toxin.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT PROPEP 25..29
FT /evidence="ECO:0000305|PubMed:25605914"
FT /id="PRO_0000439291"
FT PEPTIDE 30..52
FT /note="Con-Ins G1 B chain"
FT /evidence="ECO:0000269|PubMed:25605914"
FT /id="PRO_5002112072"
FT PROPEP 53..94
FT /note="C peptide"
FT /evidence="ECO:0000269|PubMed:25605914"
FT /id="PRO_0000439292"
FT PEPTIDE 95..114
FT /note="Con-Ins G1a A chain"
FT /evidence="ECO:0000269|PubMed:25605914"
FT /id="PRO_0000439293"
FT MOD_RES 34
FT /note="4-hydroxyproline; partial"
FT /evidence="ECO:0000269|PubMed:25605914"
FT MOD_RES 41
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:25605914"
FT MOD_RES 98
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:25605914"
FT MOD_RES 104
FT /note="4-hydroxyproline; partial"
FT /evidence="ECO:0000269|PubMed:25605914"
FT MOD_RES 109
FT /note="4-carboxyglutamate; partial"
FT /evidence="ECO:0000269|PubMed:25605914"
FT MOD_RES 114
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:25605914"
FT DISULFID 38..101
FT /note="Interchain (between B and A chains)"
FT /evidence="ECO:0000269|PubMed:27617429,
FT ECO:0007744|PDB:5JYQ"
FT DISULFID 50..114
FT /note="Interchain (between B and A chains)"
FT /evidence="ECO:0000269|PubMed:27617429,
FT ECO:0007744|PDB:5JYQ"
FT DISULFID 100..105
FT /evidence="ECO:0000269|PubMed:27617429,
FT ECO:0007744|PDB:5JYQ"
FT HELIX 96..100
FT /evidence="ECO:0007829|PDB:5JYQ"
FT TURN 101..104
FT /evidence="ECO:0007829|PDB:5JYQ"
FT HELIX 107..110
FT /evidence="ECO:0007829|PDB:5JYQ"
FT HELIX 111..113
FT /evidence="ECO:0007829|PDB:5JYQ"
SQ SEQUENCE 115 AA; 13134 MW; F578697A311DBB23 CRC64;
MTTSSYFLLM ALGLLLYVCQ SSFGNQHTRT FDTPKHRCGS EITNSYMDLC YRKRNDAGEK
RGRASPLWQR RGSLSKLKAR AKRNGAFHLP RDGRGVVEHC CHRPCSNAEF KKYCG
