TXHM3_HERML
ID TXHM3_HERML Reviewed; 35 AA.
AC C0HJK5;
DT 03-SEP-2014, integrated into UniProtKB/Swiss-Prot.
DT 03-SEP-2014, sequence version 1.
DT 25-MAY-2022, entry version 20.
DE RecName: Full=Mu-thomitoxin-Hme1c {ECO:0000305};
DE Short=Mu-TMTX-Hme1c {ECO:0000305};
DE AltName: Full=Neurotoxin Hm-3 {ECO:0000303|Ref.1};
OS Heriaeus mellotteei (Crab spider) (Heriaeus oblongus).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Entelegynae; Dionycha; Thomisidae; Heriaeus.
OX NCBI_TaxID=504442;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX DOI=10.1134/S1990747809030027;
RA Nikolsky A., Billen B., Vassilevski A., Filkin S., Tytgat J., Grishin E.;
RT "Voltage-gated sodium channels are targets for toxins from the venom of the
RT spider Heriaeus melloteei.";
RL Biochemistry (Mosc.) Suppl. Series A 3:245-253(2009).
RN [2]
RP STRUCTURE BY NMR, FUNCTION, DISULFIDE BOND, AND DOMAIN.
RC TISSUE=Venom;
RX PubMed=25352595; DOI=10.1074/jbc.m114.595678;
RA Berkut A.A., Peigneur S., Myshkin M.Y., Paramonov A.S., Lyukmanova E.N.,
RA Arseniev A.S., Grishin E.V., Tytgat J., Shenkarev Z.O., Vassilevski A.A.;
RT "Structure of membrane-active toxin from crab spider Heriaeus melloteei
RT suggests parallel evolution of sodium channel gating modifiers in
RT Araneomorphae and Mygalomorphae.";
RL J. Biol. Chem. 290:492-504(2015).
RN [3]
RP STRUCTURE BY NMR IN COMPLEX WITH HUMAN NAV1.4/SCN4A REPEAT I AND MEMBRANE,
RP FUNCTION, AND 3D-STRUCTURE MODELING IN COMPLEX WITH NAV1.4/SCN4A.
RX PubMed=29636418; DOI=10.1073/pnas.1720185115;
RA Maennikkoe R., Shenkarev Z.O., Thor M.G., Berkut A.A., Myshkin M.Y.,
RA Paramonov A.S., Kulbatskii D.S., Kuzmin D.A., Sampedro Castaneda M.,
RA King L., Wilson E.R., Lyukmanova E.N., Kirpichnikov M.P., Schorge S.,
RA Bosmans F., Hanna M.G., Kullmann D.M., Vassilevski A.A.;
RT "Spider toxin inhibits gating pore currents underlying periodic
RT paralysis.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:4495-4500(2018).
CC -!- FUNCTION: Gating-modifier toxin that inhibits mammalian and insect
CC voltage-gated sodium channels. It shifts the voltage dependence of
CC channel activation to more positive voltages. It shows potent activity
CC on Nav1.4/SCN4A (IC(50)=103 nM), Nav1.5/SCN5A (IC(50)=268 nM) and
CC Para/DmNav1 (IC(50)=555 nM) and lower activities on Nav1.2/SCN2A
CC (IC(50)=1447 nM) and Nav1.6/SCN8A (IC(50)=3504 nM) (PubMed:25352595).
CC In addition, at a concentration of 1 uM, the toxin inhibits 90-100% of
CC sodium current through Nav1.2/SCN2A, Nav1.4/SCN4A, Nav1.5/SCN5A,
CC Nav1.6/SCN8A and Para/DmNav1 channels, when the voltage of maximal
CC activation of the channel in control conditions is applied (Ref.1). It
CC binds to the S3-S4 helix-loop-helix motif in the voltage-sensing domain
CC of repeat 1 (shown on hNav1.4/SCN4A) (PubMed:29636418). The toxin is
CC amphiphilic and binds to both neutral and negatively charged lipid
CC vesicles with high affinity (PubMed:29636418, PubMed:25352595). The
CC hydrophobic face lies on the opposite side to the hydrophobic faces of
CC classical gating modifiers (PubMed:25352595).
CC {ECO:0000269|PubMed:25352595, ECO:0000269|Ref.1}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|Ref.1}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305|Ref.1}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:25352595}.
CC -!- MASS SPECTROMETRY: Mass=3907.7; Mass_error=0.5; Method=MALDI;
CC Evidence={ECO:0000269|Ref.1};
CC -!- MISCELLANEOUS: May be interesting for the development of therapies to
CC treat the periodic paralysis hypokalemic 2 (HOKPP2), since it inhibits
CC I(GP) leak currents of HOKPP2 p.R222G/W channels.
CC {ECO:0000269|PubMed:29636418}.
CC -!- MISCELLANEOUS: Does not inhibit Nav1.1/SCN1A, Nav1.3/SCN3A and
CC Nav1.8/SCN10A sodium channels, Kv1.1/KCNA1, Kv1.3/KCNA3, Kv2.1/KCNB1,
CC Kv4.2/KCND2 and Kv10.1/KCNH1 potassium channels and Cav3.3/CACNA1I
CC calcium channels when 1 uM is tested. {ECO:0000269|PubMed:25352595}.
CC -!- SIMILARITY: Belongs to the neurotoxin 07 (Beta/delta-agtx) family.
CC {ECO:0000305}.
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DR PDB; 2MQU; NMR; -; A=1-35.
DR PDBsum; 2MQU; -.
DR AlphaFoldDB; C0HJK5; -.
DR BMRB; C0HJK5; -.
DR SMR; C0HJK5; -.
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 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Secreted; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..35
FT /note="Mu-thomitoxin-Hme1c"
FT /evidence="ECO:0000269|Ref.1"
FT /id="PRO_0000430081"
FT DISULFID 2..18
FT /evidence="ECO:0000269|PubMed:25352595,
FT ECO:0000312|PDB:2MQU"
FT DISULFID 9..23
FT /evidence="ECO:0000269|PubMed:25352595,
FT ECO:0000312|PDB:2MQU"
FT DISULFID 17..34
FT /evidence="ECO:0000269|PubMed:25352595,
FT ECO:0000312|PDB:2MQU"
FT STRAND 22..26
FT /evidence="ECO:0007829|PDB:2MQU"
FT HELIX 27..29
FT /evidence="ECO:0007829|PDB:2MQU"
FT STRAND 31..35
FT /evidence="ECO:0007829|PDB:2MQU"
SQ SEQUENCE 35 AA; 3914 MW; 53D04639185F8054 CRC64;
GCIAKNKECA WFSGEWCCGA LSCKYSIKRN LKICV
