ID   INS2_CONTU              Reviewed;         115 AA.
AC   A0A3S9V8L9;
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 T2 {ECO:0000303|PubMed:30747102};
DE   AltName: Full=Insulin T2 {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins T2 B chain {ECO:0000303|PubMed:30747102};
DE   Contains:
DE     RecName: Full=Con-Ins T2 A chain {ECO:0000303|PubMed:30747102};
DE   Flags: Precursor;
OS   Conus tulipa (Fish-hunting cone snail) (Tulip cone).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC   Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX   NCBI_TaxID=6495;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SYNTHESIS OF 30-52 AND 95-114.
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 facilitates prey capture by rapidly
CC       inducing hypoglycemic shock (PubMed:30747102). It is one of the
CC       smallest known insulin found in nature and lacks the C-terminal segment
CC       of the B chain that, in human insulin, mediates engagement of the
CC       insulin receptor and assembly of the hormone's hexameric storage form
CC       (By similarity). Despite lacking this segment, it both binds and
CC       activates human insulin receptor (long isoform (HIR-B)) with a high
CC       potency (EC(50)=15.5 nM) (PubMed:30747102). In vivo, intraperitoneal
CC       injection of this peptide into zebrafish lowers blood glucose with a
CC       lower potency than human insulin (PubMed:30747102). In addition, when
CC       applied to water, this peptide reduces overall locomotor activity of
CC       zebrafish larvae, observed as a significant decrease in the percentage
CC       of time spent swimming and movement frequency (By similarity). When
CC       tested on a mouse model of diabetes, this insulin also lowers blood
CC       glucose with a 10-fold lower potency than human insulin (By
CC       similarity). {ECO:0000250|UniProtKB:A0A0B5AC95,
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:A0A0B5AC90}.
CC   -!- SIMILARITY: Belongs to the insulin family.
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DR   EMBL; MH879035; AZS18885.1; -; mRNA.
DR   AlphaFoldDB; A0A3S9V8L9; -.
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   Amidation; Carbohydrate metabolism; Cleavage on pair of basic residues;
KW   Disulfide bond; Gamma-carboxyglutamic acid; Glucose metabolism; Hormone;
KW   Hydroxylation; Secreted; Signal; Toxin.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   PROPEP          22..29
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452028"
FT   PEPTIDE         30..52
FT                   /note="Con-Ins T2 B chain"
FT                   /id="PRO_5019019994"
FT   PROPEP          53..94
FT                   /note="C peptide"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452029"
FT   PEPTIDE         95..114
FT                   /note="Con-Ins T2 A chain"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT                   /id="PRO_0000452030"
FT   MOD_RES         48
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000305"
FT   MOD_RES         98
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         109
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         114
FT                   /note="Cysteine amide"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        38..101
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        50..114
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        100..105
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
SQ   SEQUENCE   115 AA;  13070 MW;  474D6318C79195FB CRC64;
     MTTSFYFLLV ALGLLLYVCQ SSFGNQHTRN SDTPWNRCGS QITDSYRELC PHKRNDAGKK
     RGQASPLWQR GGSLSMLKAR AKRNEAFHLQ RAHRGVVEHC CKRACSNAEF MQFCG