ID   NEMA1_LINLO             Reviewed;          76 AA.
AC   P0DM24; A0A384E137;
DT   05-DEC-2018, integrated into UniProtKB/Swiss-Prot.
DT   05-DEC-2018, sequence version 1.
DT   03-AUG-2022, entry version 9.
DE   RecName: Full=Nemertide alpha-1 {ECO:0000303|PubMed:29567943};
DE   Flags: Precursor; Fragment;
OS   Lineus longissimus (Bootlace worm) (Ascaris longissima).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Nemertea; Pilidiophora;
OC   Heteronemertea; Lineidae; Lineus.
OX   NCBI_TaxID=88925;
RN   [1] {ECO:0000312|PDB:6ENA}
RP   NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 45-75, FUNCTION, MASS
RP   SPECTROMETRY, HYDROXYLATION AT PRO-72 AND PRO-73, SYNTHESIS OF 45-75,
RP   STRUCTURE BY NMR OF 45-75, AND BIOASSAY.
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], FUNCTION, SYNTHESIS OF 45-75, 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).
RN   [3]
RP   EFFECT IN BRUGADA SYNDROME 1, AND SYNTHESIS OF 45-75.
RX   PubMed=32850980; DOI=10.3389/fcvm.2020.00117;
RA   Nijak A., Labro A.J., De Wilde H., Dewals W., Peigneur S., Tytgat J.,
RA   Snyders D., Sieliwonczyk E., Simons E., Van Craenenbroeck E., Schepers D.,
RA   Van Laer L., Saenen J., Loeys B., Alaerts M.;
RT   "Compound heterozygous SCN5A mutations in severe sodium channelopathy with
RT   Brugada syndrome: a case report.";
RL   Front. Cardiovasc. Med. 7:117-117(2020).
CC   -!- FUNCTION: Highly potent toxin against insect sodium channel (Nav) and
CC       with less potent activity against mammalian sodium channels
CC       (PubMed:29567943). Potently inhibits inactivation of insect sodium
CC       channels of B.germanica (BgNav1) (EC(50)=8.6 nM), D.melanogaster
CC       (DmNav1), and arachnid sodium channel V.destructor (VdNav1)
CC       (PubMed:29567943, PubMed:34445875). Also delays the inactivation of
CC       most mammalian Nav channels tested (hNav1.1/SCN1A; EC(50)=124.1 nM,
CC       rNav1.2/SCN2A; EC(50)=359.6 nM, rNav1.3/SCN3A; EC(50)=135.4 nM,
CC       rNav1.4/SCN4A; EC(50)=145.5 nM, hNav1.5/SCN5A; EC(50)=138.3 nM,
CC       mNav1.6/SCN8A; EC(50)=240.4 nM, hNav1.9/SCN9A; EC(50)=76.5 nM)
CC       (PubMed:29567943, PubMed:34445875). 1 uM is enough to completely
CC       inhibits the inactivation, resulting in sustained non-inactivating
CC       currents (PubMed:29567943). In addition, the toxin significantly
CC       enhances the recovery from inactivation, and the open state is not
CC       required for the toxin to interact with the channel (PubMed:29567943).
CC       In vivo, injection into green crabs (Carcinus maenas at 1 mug/kg) of
CC       small doses (1-5 ug/kg) results in slow and fast permanent paralysis,
CC       whereas injection of high doses (more than 10 ug/kg) causes death
CC       (PubMed:29567943). Injection into juvenile Blaptica dubia cockroaches
CC       results in death or permanent paralysis at doses higher than 7.1 ug/kg
CC       (PubMed:29567943). Injection into brine shrimp (Artemia salina) stops
CC       movement or causes death after 24 hours (EC(50)=0.3 uM)
CC       (PubMed:34445875). In the rare inherited cardiac arrhythmia Brugada
CC       syndrome 1 (BRGDA1), this toxin is able to restore the loss of function
CC       by reducing channel inactivation, without affecting activation, by
CC       binding to Nav1.5/SCN5A (PubMed:32850980).
CC       {ECO:0000269|PubMed:29567943, ECO:0000269|PubMed:32850980,
CC       ECO:0000269|PubMed:34445875}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:29567943}.
CC   -!- TISSUE SPECIFICITY: Confined to the epidermis and to the mucus layer.
CC       {ECO:0000269|PubMed:29567943}.
CC   -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC       structurally defines this protein as a knottin.
CC       {ECO:0000305|PubMed:29567943}.
CC   -!- MASS SPECTROMETRY: Mass=3308.767; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:29567943};
CC   -!- MISCELLANEOUS: Does not shows effect on both human and rat
CC       Nav1.8/SCN10A. {ECO:0000269|PubMed:29567943,
CC       ECO:0000269|PubMed:34445875}.
CC   -!- SIMILARITY: Belongs to the nemertide family. {ECO:0000305}.
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DR   PDB; 6ENA; NMR; -; A=45-75.
DR   PDBsum; 6ENA; -.
DR   AlphaFoldDB; P0DM24; -.
DR   SMR; P0DM24; -.
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.
DR   PROSITE; PS60004; OMEGA_CONOTOXIN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Cleavage on pair of basic residues;
KW   Direct protein sequencing; Disulfide bond; Hydroxylation;
KW   Ion channel impairing toxin; Knottin; Secreted; Signal; Toxin;
KW   Voltage-gated sodium channel impairing toxin.
FT   SIGNAL          <1..28
FT                   /evidence="ECO:0000255"
FT   PROPEP          29..44
FT                   /evidence="ECO:0000305|PubMed:29567943"
FT                   /id="PRO_0000445910"
FT   CHAIN           45..75
FT                   /note="Nemertide alpha-1"
FT                   /evidence="ECO:0000269|PubMed:29567943"
FT                   /id="PRO_0000445911"
FT   SITE            52
FT                   /note="Hydrophobic/aromatic residue important for potent
FT                   activity"
FT                   /evidence="ECO:0000305|PubMed:34445875"
FT   MOD_RES         72
FT                   /note="4-hydroxyproline"
FT                   /evidence="ECO:0000269|PubMed:29567943"
FT   MOD_RES         73
FT                   /note="4-hydroxyproline"
FT                   /evidence="ECO:0000269|PubMed:29567943"
FT   DISULFID        46..60
FT                   /evidence="ECO:0000269|PubMed:29567943,
FT                   ECO:0000312|PDB:6ENA"
FT   DISULFID        53..64
FT                   /evidence="ECO:0000269|PubMed:29567943,
FT                   ECO:0000312|PDB:6ENA"
FT   DISULFID        59..70
FT                   /evidence="ECO:0000269|PubMed:29567943,
FT                   ECO:0000312|PDB:6ENA"
FT   NON_TER         1
FT   HELIX           56..58
FT                   /evidence="ECO:0007829|PDB:6ENA"
FT   STRAND          68..70
FT                   /evidence="ECO:0007829|PDB:6ENA"
SQ   SEQUENCE   76 AA;  8232 MW;  AC0E50EBF6BAD776 CRC64;
     YRIASSSIAK MKTAVFLVGL LFLGLVFADE AAIDSEFDQS IDKRGCIATG SFCTLSKGCC
     TKNCGWNFKC NPPNQK