ID   CRFA2_CONTE             Reviewed;          72 AA.
AC   P0DM27;
DT   13-FEB-2019, integrated into UniProtKB/Swiss-Prot.
DT   13-FEB-2019, sequence version 1.
DT   25-MAY-2022, entry version 8.
DE   RecName: Full=Conorfamide-Tx2 {ECO:0000250|UniProtKB:P0DOZ7, ECO:0000303|PubMed:30243794};
DE            Short=CNF-Tx2 {ECO:0000303|PubMed:30243794};
DE   AltName: Full=Cono-RFamide-Tx2 {ECO:0000250|UniProtKB:P0DOZ7, ECO:0000303|PubMed:30243794};
DE   Flags: Precursor;
OS   Conus textile (Cloth-of-gold cone).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC   Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Cylinder.
OX   NCBI_TaxID=6494;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, BIOASSAY, AND SYNTHESIS OF 26-43.
RX   PubMed=30243794; DOI=10.1016/j.toxicon.2018.09.002;
RA   Espino S.S., Robinson S.D., Safavi-Hemami H., Gajewiak J., Yang W.,
RA   Olivera B.M., Liu Q.;
RT   "Conopeptides promote itch through human itch receptor hMgprX1.";
RL   Toxicon 154:28-34(2018).
RN   [2]
RP   FUNCTION, AND SYNTHESIS OF 26-43.
RX   PubMed=33764053; DOI=10.1021/acs.jnatprod.0c01297;
RA   Bosse G.D., Urcino C., Watkins M., Florez Salcedo P., Kozel S., Chase K.,
RA   Cabang A., Espino S.S., Safavi-Hemami H., Raghuraman S., Olivera B.M.,
RA   Peterson R.T., Gajewiak J.;
RT   "Discovery of a potent conorfamide from Conus episcopatus using a novel
RT   zebrafish larvae assay.";
RL   J. Nat. Prod. 84:1232-1243(2021).
CC   -!- FUNCTION: This peptide activates human sensory neuron-specific G-
CC       protein coupled receptors MRGPRX1, but not mouse receptors (EC(50)=0.54
CC       uM) (PubMed:30243794). Compared with the agonist chloroquine (anti-
CC       malaria drug), it is 600-fold more potent (PubMed:30243794). In vivo,
CC       induces itch sensation, since intradermal cheek injection into
CC       humanized transgenic mouse (mouse MRGPRX1 replaced by human MRGPRX1)
CC       induces scratching (PubMed:30243794). In vivo, treatment of zebrafish
CC       larvae with high doses (10 uM) induces hypoactivity at the beginning of
CC       the experiment during the dark phase and hyperactivity in the strobe
CC       phase after one hour, even after the removal of the toxin from the
CC       solution (PubMed:33764053). {ECO:0000269|PubMed:30243794,
CC       ECO:0000269|PubMed:33764053}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:30243794}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC       {ECO:0000305|PubMed:30243794}.
CC   -!- MISCELLANEOUS: The mature peptide does not contain cysteine residue.
CC       {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the FARP (FMRFamide related peptide) family.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Protein Spotlight; Note=Paths of discomfort - Issue
CC       212 of March 2019;
CC       URL="https://web.expasy.org/spotlight/back_issues/212/";
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DR   AlphaFoldDB; P0DM27; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE   3: Inferred from homology;
KW   Amidation; Cleavage on pair of basic residues;
KW   G-protein coupled receptor impairing toxin; Neurotoxin; Secreted; Signal;
KW   Toxin.
FT   SIGNAL          1..19
FT                   /evidence="ECO:0000255"
FT   PROPEP          20..25
FT                   /evidence="ECO:0000305|PubMed:30243794"
FT                   /id="PRO_0000446247"
FT   PEPTIDE         26..43
FT                   /note="Conorfamide-Tx2"
FT                   /evidence="ECO:0000305|PubMed:30243794"
FT                   /id="PRO_0000446248"
FT   PROPEP          44..72
FT                   /evidence="ECO:0000305|PubMed:30243794"
FT                   /id="PRO_0000446249"
FT   REGION          32..39
FT                   /note="Positively charged region crucial for activity
FT                   against MRGPRX1 receptors"
FT                   /evidence="ECO:0000305|PubMed:30243794"
FT   SITE            43
FT                   /note="Key residue for high activating potency against
FT                   MRGPRX1 receptors"
FT                   /evidence="ECO:0000305|PubMed:30243794"
FT   MOD_RES         43
FT                   /note="Isoleucine amide"
FT                   /evidence="ECO:0000250|UniProtKB:P0DOZ7"
SQ   SEQUENCE   72 AA;  8248 MW;  97B5A401B04AF558 CRC64;
     MSGRGFLLLA LLLLVTVEAT RVEKKHSGIL LAWSGPRNRF VRIGRRDMQS PLLSERLRFR
     ALGFRQPSSQ KQ