ID   INS1_CONKI              Reviewed;         108 AA.
AC   A0A3S9V8L7;
DT   10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT   08-MAY-2019, sequence version 1.
DT   03-AUG-2022, entry version 11.
DE   RecName: Full=Con-Ins K1 {ECO:0000303|PubMed:30747102};
DE   AltName: Full=Insulin K1 {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins K1 B chain {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins K1 A chain {ECO:0000303|PubMed:30747102};
DE   Flags: Precursor;
OS   Conus kinoshitai (Kinoshita's cone).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC   Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Afonsoconus.
OX   NCBI_TaxID=376876;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SYNTHESIS OF 29-56 AND 84-107, AND
RP   3D-STRUCTURE MODELING IN 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).
CC   -!- FUNCTION: This venom insulin, from a fish-hunting cone snail,
CC       facilitates prey capture by rapidly inducing hypoglycemic shock
CC       (PubMed:30747102). It is one of the smallest known insulin found in
CC       nature and lacks the C-terminal segment of the B chain that, in human
CC       insulin, mediates engagement of the insulin receptor and assembly of
CC       the hormone's hexameric storage form (By similarity). Despite lacking
CC       this segment, it both binds and activates human insulin receptor (long
CC       isoform (HIR-B)) with a moderate potency (EC(50)=30.45 nM)
CC       (PubMed:30747102). In vivo, intraperitoneal injection of this peptide
CC       into zebrafish lowers blood glucose with a lower potency than human
CC       insulin (PubMed:30747102). In addition, when applied to water, this
CC       peptide reduces overall locomotor activity of zebrafish larvae,
CC       observed as a significant decrease in the percentage of time spent
CC       swimming and movement frequency (By similarity). When tested on a mouse
CC       model of diabetes, this insulin also lowers blood glucose with a 20-
CC       fold lower potency than human insulin (PubMed:30747102).
CC       {ECO:0000250|UniProtKB:A0A0B5AC95, ECO:0000269|PubMed:30747102}.
CC   -!- SUBUNIT: Heterodimer of A and B chains; disulfide-linked.
CC       {ECO:0000250|UniProtKB:A0A0B5AC95}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:A0A0B5AC95}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC       {ECO:0000250|UniProtKB:A0A0B5AC95}.
CC   -!- SIMILARITY: Belongs to the insulin family. {ECO:0000305}.
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DR   EMBL; MH879033; AZS18883.1; -; mRNA.
DR   AlphaFoldDB; A0A3S9V8L7; -.
DR   SMR; A0A3S9V8L7; -.
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; IPR016724; Insulin-rel_pep.
DR   InterPro; IPR022353; Insulin_CS.
DR   InterPro; IPR022352; Insulin_family.
DR   Pfam; PF00049; Insulin; 1.
DR   PIRSF; PIRSF018431; Molluscan_insulin_rel_peptide; 1.
DR   PRINTS; PR00276; INSULINFAMLY.
DR   SMART; SM00078; IlGF; 1.
DR   SUPFAM; SSF56994; SSF56994; 1.
DR   PROSITE; PS00262; INSULIN; 1.
PE   3: Inferred from homology;
KW   Amidation; Carbohydrate metabolism; Cleavage on pair of basic residues;
KW   Disulfide bond; Gamma-carboxyglutamic acid; Glucose metabolism; Hormone;
KW   Secreted; Signal; Toxin.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000255"
FT   PROPEP          25..28
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452031"
FT   PEPTIDE         29..56
FT                   /note="Con-Ins K1 B chain"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_5019276852"
FT   PROPEP          57..83
FT                   /note="C peptide"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452032"
FT   PEPTIDE         84..107
FT                   /note="Con-Ins K1 A chain"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452033"
FT   MOD_RES         44
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         87
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         107
FT                   /note="Glutamine amide"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        41..90
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        53..103
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        89..94
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
SQ   SEQUENCE   108 AA;  12135 MW;  73E90DF993B311C2 CRC64;
     MTTSSYFLLV ALGLLLYVCQ SSFGSPHTSD SGTTLVRRRL CGSELVTYLG ELCLGNRKRR
     GFPSMLKARA KRNEAFLLQR DGRGIVEDCC YNDCTDEKLK EYCHTLQG