ID   INS2_CONKI              Reviewed;         109 AA.
AC   A0A3S9V8K6;
DT   10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT   08-MAY-2019, sequence version 1.
DT   25-MAY-2022, entry version 10.
DE   RecName: Full=Con-Ins K2 {ECO:0000303|PubMed:30747102};
DE   AltName: Full=Insulin K2 {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins K2 B chain {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins K2 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, AND SYNTHESIS OF 30-56 AND 84-109.
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)=373.2 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 (By similarity).
CC       {ECO:0000250|UniProtKB:A0A0B5AC95, ECO:0000250|UniProtKB:A0A3S9V8L7,
CC       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; MH879034; AZS18884.1; -; mRNA.
DR   AlphaFoldDB; A0A3S9V8K6; -.
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   Pfam; PF00049; Insulin; 1.
DR   SMART; SM00078; IlGF; 1.
DR   SUPFAM; SSF56994; SSF56994; 1.
DR   PROSITE; PS00262; INSULIN; 1.
PE   3: Inferred from homology;
KW   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..29
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452034"
FT   PEPTIDE         30..56
FT                   /note="Con-Ins K2 B chain"
FT                   /id="PRO_5019458389"
FT   PROPEP          57..83
FT                   /note="C peptide"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452035"
FT   PEPTIDE         84..109
FT                   /note="Con-Ins K2 A chain"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452036"
FT   MOD_RES         44
FT                   /note="4-carboxyglutamate"
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   109 AA;  12121 MW;  5DFA73145A36E237 CRC64;
     MTTSSYFLLV ALGLLLYVCQ SSFGNPHTRD SGTTPDRDHS CGGELVDRLV KLCPSNRKRR
     GFPSMLKARA KRNEAFLLQR DGRVIVGDCC DNYCTDERLK GYCASLLGL