ID   NEMA6_LINSA             Reviewed;          31 AA.
AC   P0DQS8;
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-6 {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 both insect and some mammalian
CC       sodium channels (Nav) (PubMed:34445875). It potently inhibits
CC       inactivation of insect sodium channels of B.germanica (BgNav1)
CC       (EC(50)=2.6 nM) and also delays the inactivation of mammalian Nav with
CC       potent activity on Nav1.1/SCN1A (hNav1.1/SCN1A; EC(50)=7.9 nM,
CC       rNav1.2/SCN2A; EC(50)=24.3 nM, rNav1.3/SCN3A; EC(50)=105.6 nM,
CC       rNav1.4/SCN4A; EC(50)=46.4 nM, hNav1.5/SCN5A; EC(50)=215.2 nM,
CC       mNav1.6/SCN8A; EC(50)=36.3 nM, hNav1.9/SCN9A; EC(50)=97.2 nM)
CC       (PubMed:34445875). 1 uM is enough to completely inhibits the
CC       inactivation, resulting in sustained non-inactivating currents (By
CC       similarity). In addition, the toxin significantly enhances the recovery
CC       from inactivation, and the open state is not required for the toxin to
CC       interact with the channel (By similarity). In vivo, injection into
CC       brine shrimp (Artemia salina) stops movement or causes death after 24
CC       hours (EC(50)=2.8 uM) (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-6"
FT                   /evidence="ECO:0000305|PubMed:29567943"
FT                   /id="PRO_0000454429"
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;  3350 MW;  D973BBD0335ECABB CRC64;
     GCIKTGSFCT LSKGCCTKNC GWNFHCNPPN Q