NEMA1_LINLC
ID NEMA1_LINLC Reviewed; 76 AA.
AC P0DQS1;
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-1 {ECO:0000303|PubMed:29567943};
DE Flags: Precursor; Fragment;
OS Lineus lacteus (Ribbon worm) (Ramphogordius lacteus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Nemertea; Pilidiophora;
OC Heteronemertea; Lineidae; Ramphogordius.
OX NCBI_TaxID=947578;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MASS SPECTROMETRY, HYDROXYLATION AT
RP PRO-72 AND PRO-73, SYNTHESIS 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], SYNTHESIS OF 45-75, AND FUNCTION.
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 -!- MISCELLANEOUS: The primary and 3D structures of the mature peptide is
CC identical to that of Nemertide alpha-1 from Lineus longissimus (AC
CC P0DM24). Links to the 3D-structure (PDB=6ENA) is available in this
CC entry. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the nemertide family. {ECO:0000305}.
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DR SMR; P0DQS1; -.
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 1: Evidence at protein level;
KW Cleavage on pair of basic residues; 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_0000454420"
FT CHAIN 45..75
FT /note="Nemertide alpha-1"
FT /evidence="ECO:0000269|PubMed:29567943"
FT /id="PRO_0000454421"
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 DISULFID 53..64
FT /evidence="ECO:0000269|PubMed:29567943"
FT DISULFID 59..70
FT /evidence="ECO:0000269|PubMed:29567943"
FT NON_TER 1
SQ SEQUENCE 76 AA; 8232 MW; AC0E50EBF6BAD776 CRC64;
YRIASSSIAK MKTAVFLVGL LFLGLVFADE AAIDSEFDQS IDKRGCIATG SFCTLSKGCC
TKNCGWNFKC NPPNQK
