ID   NEMA4_LINSA             Reviewed;          31 AA.
AC   P0DQS6;
DT   23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT   23-FEB-2022, sequence version 1.
DT   03-AUG-2022, entry version 2.
DE   RecName: Full=Nemertide alpha-4 {ECO:0000303|PubMed:34445875};
OS   Lineus sanguineus (Ribbon worm).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Nemertea; Pilidiophora;
OC   Heteronemertea; Lineidae; Lineus.
OX   NCBI_TaxID=187800;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=29567943; DOI=10.1038/s41598-018-22305-w;
RA   Jacobsson E., Andersson H.S., Strand M., Peigneur S., Eriksson C.,
RA   Loden H., Shariatgorji M., Andren P.E., Lebbe E.K.M., Rosengren K.J.,
RA   Tytgat J., Goeransson U.;
RT   "Peptide ion channel toxins from the bootlace worm, the longest animal on
RT   Earth.";
RL   Sci. Rep. 8:4596-4596(2018).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS, FUNCTION, AND BIOASSAY.
RX   PubMed=34445875; DOI=10.1021/acs.jnatprod.1c00104;
RA   Jacobsson E., Peigneur S., Andersson H.S., Laborde Q., Strand M.,
RA   Tytgat J., Goeransson U.;
RT   "Functional characterization of the nemertide alpha family of peptide
RT   toxins.";
RL   J. Nat. Prod. 84:2121-2128(2021).
CC   -!- FUNCTION: Highly potent toxin against insect sodium channel (Nav) and
CC       with less potent against some mammalian Nav (PubMed:34445875). Potently
CC       inhibits inactivation of insect sodium channels of B.germanica (BgNav1)
CC       (EC(50)=11.1 nM) (PubMed:34445875). Also delays the inactivation of
CC       most mammalian Nav (hNav1.1/SCN1A; EC(50)=92 nM, rNav1.2/SCN2A;
CC       EC(50)=134.2 nM, rNav1.3/SCN3A; EC(50)=12.9 nM, rNav1.4/SCN4A;
CC       EC(50)=14.6 nM, hNav1.5/SCN5A; EC(50)=27.8 nM, mNav1.6/SCN8A;
CC       EC(50)=123.6 nM, hNav1.9/SCN9A; EC(50)=80.5 nM) (PubMed:34445875). 1 uM
CC       is enough to completely inhibits the inactivation, resulting in
CC       sustained non-inactivating currents (By similarity). In addition, the
CC       toxin significantly enhances the recovery from inactivation, and the
CC       open state is not required for the toxin to interact with the channel
CC       (By similarity). In vivo, injection into brine shrimp (Artemia salina)
CC       stops movement or causes death after 24 hours (EC(50)=0.4 uM)
CC       (PubMed:34445875). {ECO:0000250|UniProtKB:P0DM24,
CC       ECO:0000269|PubMed:34445875}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P0DM24}.
CC   -!- TISSUE SPECIFICITY: Confined to the epidermis and to the mucus layer.
CC       {ECO:0000250|UniProtKB:P0DM24}.
CC   -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC       structurally defines this protein as a knottin.
CC       {ECO:0000250|UniProtKB:P0DM24}.
CC   -!- MISCELLANEOUS: Does not shows effect on rat Nav1.8/SCN10A.
CC       {ECO:0000269|PubMed:34445875}.
CC   -!- SIMILARITY: Belongs to the nemertide family. {ECO:0000305}.
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DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE   3: Inferred from homology;
KW   Disulfide bond; Hydroxylation; Ion channel impairing toxin; Knottin;
KW   Secreted; Toxin; Voltage-gated sodium channel impairing toxin.
FT   CHAIN           1..31
FT                   /note="Nemertide alpha-4"
FT                   /evidence="ECO:0000305|PubMed:29567943"
FT                   /id="PRO_0000454427"
FT   SITE            8
FT                   /note="Hydrophobic/aromatic residue important for potent
FT                   activity"
FT                   /evidence="ECO:0000305|PubMed:34445875"
FT   MOD_RES         28
FT                   /note="4-hydroxyproline"
FT                   /evidence="ECO:0000250|UniProtKB:P0DM24"
FT   MOD_RES         29
FT                   /note="4-hydroxyproline"
FT                   /evidence="ECO:0000250|UniProtKB:P0DM24"
FT   DISULFID        2..16
FT                   /evidence="ECO:0000250|UniProtKB:P0DM24"
FT   DISULFID        9..20
FT                   /evidence="ECO:0000250|UniProtKB:P0DM24"
FT   DISULFID        15..26
FT                   /evidence="ECO:0000250|UniProtKB:P0DM24"
SQ   SEQUENCE   31 AA;  3300 MW;  D973BBC9B2C6C86B CRC64;
     GCISTGSFCT LSKGCCTKNC GWNFKCNPPN Q