ID   INS3A_CONGE             Reviewed;         113 AA.
AC   A0A0B5A8P4;
DT   15-MAR-2017, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-2015, sequence version 1.
DT   25-MAY-2022, entry version 23.
DE   RecName: Full=Con-Ins G3 {ECO:0000303|PubMed:25605914};
DE   AltName: Full=Insulin 3 {ECO:0000312|EMBL:AJD85820.1};
DE   Contains:
DE     RecName: Full=Con-Ins G3 B chain {ECO:0000303|PubMed:25605914};
DE   Contains:
DE     RecName: Full=Con-Ins G3 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 30-51 AND 93-113, MASS
RP   SPECTROMETRY, AMIDATION AT HIS-51, GAMMA-CARBOXYGLUTAMATION AT GLU-96,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
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, AND SYNTHESIS OF 30-51 AND 93-113.
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 high potency (EC(50)=242 nM) (PubMed:30747102).
CC       In vivo, intraperitoneal injection of this peptide into zebrafish
CC       lowers blood glucose with a lower potency than human insulin
CC       (PubMed:30747102). In addition, when applied to water, this peptide
CC       reduces overall locomotor activity of zebrafish larvae, observed as a
CC       significant decrease in the percentage of time spent swimming and
CC       movement frequency (By similarity). When tested on a mouse model of
CC       diabetes, this insulin also lowers blood glucose with a 10-fold lower
CC       potency than human insulin (By similarity).
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:0000269|PubMed:25605914}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC       {ECO:0000305|PubMed:25605914}.
CC   -!- PTM: It is noteworthy that in this dimer, in contrast to Con-Ins G1,
CC       the chain B is amidated and not the chain A.
CC       {ECO:0000269|PubMed:25605914}.
CC   -!- MASS SPECTROMETRY: Mass=4817.1; Method=Electrospray; Note=without
CC       hydroxyPro and with 3 carboxyglutamate (residues 41, 98 and 109). The
CC       measured ranges are 30-51, 93-113.;
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.
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DR   EMBL; KP268616; AJD85820.1; -; mRNA.
DR   AlphaFoldDB; A0A0B5A8P4; -.
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   Amidation; Carbohydrate metabolism; Cleavage on pair of basic residues;
KW   Direct protein sequencing; Disulfide bond; Gamma-carboxyglutamic acid;
KW   Glucose metabolism; Hormone; Hydroxylation; Secreted; Signal; Toxin.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   PROPEP          22..29
FT                   /evidence="ECO:0000305"
FT                   /id="PRO_0000439310"
FT   PEPTIDE         30..51
FT                   /note="Con-Ins G3 B chain"
FT                   /evidence="ECO:0000269|PubMed:25605914"
FT                   /id="PRO_5002112025"
FT   PROPEP          52..92
FT                   /note="C peptide"
FT                   /evidence="ECO:0000269|PubMed:25605914"
FT                   /id="PRO_0000439311"
FT   PEPTIDE         93..113
FT                   /note="Con-Ins G3 A chain"
FT                   /evidence="ECO:0000269|PubMed:25605914"
FT                   /id="PRO_0000439312"
FT   MOD_RES         34
FT                   /note="4-hydroxyproline; partial"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         41
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   MOD_RES         51
FT                   /note="Histidine amide"
FT                   /evidence="ECO:0000269|PubMed:25605914,
FT                   ECO:0000269|PubMed:30747102"
FT   MOD_RES         96
FT                   /note="4-carboxyglutamate"
FT                   /evidence="ECO:0000269|PubMed:25605914,
FT                   ECO:0000269|PubMed:30747102"
FT   MOD_RES         102
FT                   /note="4-hydroxyproline; partial"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        38..99
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        50..112
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
FT   DISULFID        98..103
FT                   /evidence="ECO:0000250|UniProtKB:A0A0B5AC95"
SQ   SEQUENCE   113 AA;  12817 MW;  600FDBADF86CBFE8 CRC64;
     MTTSFYFLLV ALGLLLYVCQ SSFGNQHTRN SDTPKHRCGS ELADQYVQLC HGKRNDAGKK
     RGRASPLWQR QGFLSMLKAK RNEAFFLQRD GRGIVEVCCD NPCTVATLRT FCH