MTX4_GRARO
ID MTX4_GRARO Reviewed; 82 AA.
AC Q7YT39; Q7M3T1;
DT 16-JAN-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2003, sequence version 1.
DT 25-MAY-2022, entry version 93.
DE RecName: Full=M-theraphotoxin-Gr1a {ECO:0000305};
DE Short=M-TRTX-Gr1a {ECO:0000305};
DE AltName: Full=GsMTx-4 {ECO:0000303|PubMed:10779316, ECO:0000303|PubMed:11343101, ECO:0000303|PubMed:12082099, ECO:0000303|PubMed:16376854};
DE Short=GsMTx4 {ECO:0000303|PubMed:14559077, ECO:0000303|PubMed:15241420, ECO:0000303|PubMed:15287735, ECO:0000303|PubMed:16797839, ECO:0000303|PubMed:17384064, ECO:0000303|PubMed:19955179, ECO:0000303|PubMed:21740921};
DE Short=MTx4;
DE AltName: Full=GsMTx-IV {ECO:0000303|PubMed:29703751};
DE Flags: Precursor;
OS Grammostola rosea (Chilean rose tarantula) (Grammostola spatulata).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Grammostola.
OX NCBI_TaxID=432528;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SYNTHESIS OF 47-80.
RC TISSUE=Venom gland;
RX PubMed=14559077; DOI=10.1016/s0041-0101(03)00141-7;
RA Ostrow K.L., Mammoser A., Suchyna T.M., Sachs F., Oswald R.E., Kubo S.,
RA Chino N., Gottlieb P.A.;
RT "cDNA sequence and in vitro folding of GsMTx4, a specific peptide inhibitor
RT of mechanosensitive channels.";
RL Toxicon 42:263-274(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=21740921; DOI=10.1016/j.toxicon.2011.06.006;
RA Ono S., Kimura T., Kubo T.;
RT "Characterization of voltage-dependent calcium channel blocking peptides
RT from the venom of the tarantula Grammostola rosea.";
RL Toxicon 58:265-276(2011).
RN [3]
RP PROTEIN SEQUENCE OF 47-81, FUNCTION, MASS SPECTROMETRY, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Venom;
RX PubMed=10779316; DOI=10.1085/jgp.115.5.583;
RA Suchyna T.M., Johnson J.H., Hamer K., Leykam J.F., Gage D.A., Clemo H.F.,
RA Baumgarten C.M., Sachs F.;
RT "Identification of a peptide toxin from Grammostola spatulata spider venom
RT that blocks cation-selective stretch-activated channels.";
RL J. Gen. Physiol. 115:583-598(2000).
RN [4]
RP ERRATUM OF PUBMED:10779316, AND SEQUENCE REVISION.
RA Suchyna T.M., Johnson J.H., Hamer K., Leykam J.F., Gage D.A., Clemo H.F.,
RA Baumgarten C.M., Sachs F.;
RL J. Gen. Physiol. 117:371-371(2001).
RN [5]
RP PROTEIN SEQUENCE OF 47-81.
RC TISSUE=Venom;
RA Sachs F., Johnson J.H., Suchyna T.M.;
RT "Mechanically activated channel blocker.";
RL Patent number US0077286, 20-JUN-2002.
RN [6]
RP PROTEIN SEQUENCE OF 47-80, STRUCTURE BY NMR OF 47-80, DISULFIDE BONDS,
RP AMIDATION AT PHE-80, SEQUENCE REVISION IN PROOF, AND MASS SPECTROMETRY.
RX PubMed=12082099; DOI=10.1074/jbc.m202715200;
RA Oswald R.E., Suchyna T.M., McFeeters R., Gottlieb P.A., Sachs F.;
RT "Solution structure of peptide toxins that block mechanosensitive ion
RT channels.";
RL J. Biol. Chem. 277:34443-34450(2002).
RN [7]
RP PROTEIN SEQUENCE OF 47-80, FUNCTION, AMIDATION AT PHE-80, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=19955179; DOI=10.1074/jbc.m109.054718;
RA Redaelli E., Cassulini R.R., Silva D.F., Clement H., Schiavon E.,
RA Zamudio F.Z., Odell G., Arcangeli A., Clare J.J., Alagon A.,
RA de la Vega R.C., Possani L.D., Wanke E.;
RT "Target promiscuity and heterogeneous effects of tarantula venom peptides
RT affecting Na+ and K+ ion channels.";
RL J. Biol. Chem. 285:4130-4142(2010).
RN [8]
RP ERRATUM OF PUBMED:19955179, AND SEQUENCE REVISION.
RA Redaelli E., Cassulini R.R., Silva D.F., Clement H., Schiavon E.,
RA Zamudio F.Z., Odell G., Arcangeli A., Clare J.J., Alagon A.,
RA de la Vega R.C., Possani L.D., Wanke E.;
RL J. Biol. Chem. 285:13314-13314(2010).
RN [9]
RP FUNCTION.
RX PubMed=11343101; DOI=10.1038/35051165;
RA Bode F., Sachs F., Franz M.R.;
RT "Tarantula peptide inhibits atrial fibrillation.";
RL Nature 409:35-36(2001).
RN [10]
RP FUNCTION.
RC TISSUE=Venom;
RX PubMed=15287735; DOI=10.1021/bi049463y;
RA Ruta V., MacKinnon R.;
RT "Localization of the voltage-sensor toxin receptor on KvAP.";
RL Biochemistry 43:10071-10079(2004).
RN [11]
RP FUNCTION, MEMBRANE-PARTITIONING, AND D-GSMTX4 SYNTHESIS.
RX PubMed=15241420; DOI=10.1038/nature02743;
RA Suchyna T.M., Tape S.E., Koeppe R.E. II, Andersen O.S., Sachs F.,
RA Gottlieb P.A.;
RT "Bilayer-dependent inhibition of mechanosensitive channels by neuroactive
RT peptide enantiomers.";
RL Nature 430:235-240(2004).
RN [12]
RP FUNCTION.
RX PubMed=16376854; DOI=10.1016/j.bbrc.2005.12.046;
RA Jung H.J., Kim P.I., Lee S.K., Lee C.W., Eu Y.J., Lee D.G., Earm Y.E.,
RA Kim J.I.;
RT "Lipid membrane interaction and antimicrobial activity of GsMTx-4, an
RT inhibitor of mechanosensitive channel.";
RL Biochem. Biophys. Res. Commun. 340:633-638(2006).
RN [13]
RP FUNCTION ON THE MEMBRANE MOTOR OF OUTER HAIR CELLS.
RX PubMed=16797839; DOI=10.1016/j.neulet.2006.05.059;
RA Fang J., Iwasa K.H.;
RT "Effects of tarantula toxin GsMTx4 on the membrane motor of outer hair
RT cells.";
RL Neurosci. Lett. 404:213-216(2006).
RN [14]
RP FUNCTION.
RX PubMed=17384064; DOI=10.1529/biophysj.106.101071;
RA Nishizawa M., Nishizawa K.;
RT "Molecular dynamics simulations of a stretch-activated channel inhibitor
RT GsMTx4 with lipid membranes: two binding modes and effects of lipid
RT structure.";
RL Biophys. J. 92:4233-4243(2007).
RN [15]
RP FUNCTION.
RX PubMed=17573432; DOI=10.1529/biophysj.107.112375;
RA Posokhov Y.O., Gottlieb P.A., Morales M.J., Sachs F., Ladokhin A.S.;
RT "Is lipid bilayer binding a common property of inhibitor cysteine knot ion-
RT channel blockers?";
RL Biophys. J. 93:L20-L22(2007).
RN [16]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=29703751; DOI=10.1074/jbc.ra118.002553;
RA Agwa A.J., Peigneur S., Chow C.Y., Lawrence N., Craik D.J., Tytgat J.,
RA King G.F., Henriques S.T., Schroeder C.I.;
RT "Gating modifier toxins isolated from spider venom: modulation of voltage-
RT gated sodium channels and the role of lipid membranes.";
RL J. Biol. Chem. 293:9041-9052(2018).
RN [17]
RP FUNCTION ON ACHR, AND SYNTHESIS OF 47-80.
RX PubMed=34374321; DOI=10.1080/19336950.2021.1961459;
RA Pan N.C., Zhang T., Hu S., Liu C., Wang Y.;
RT "Fast desensitization of acetylcholine receptors induced by a spider
RT toxin.";
RL Channels 15:507-515(2021).
RN [18]
RP STRUCTURE BY NMR OF 47-80, AND DISULFIDE BONDS.
RA Jung H.J., Lee C.W., Earm Y.E., Kim J.I.;
RT "Solution structure of GsMTx-4, a peptide blocker of cation-selective
RT stretch-activated channels.";
RL Submitted (MAY-2002) to the PDB data bank.
CC -!- FUNCTION: This cationic hydrophobic peptide acts on a lot of different
CC channels and has an antimicrobial activity. It blocks mechanosensitive
CC ion channels (also named stretch-activated channels or SACs), without
CC having effect on whole-cell voltage-sensitive currents. It also affects
CC acetylcholine receptors (nAChRs) through interactions with membrane
CC lipids by prolonging the closing time without affecting channel
CC conductance or opening activity (PubMed:34374321). It shows high
CC affinity for lipid bilayers (PubMed:15241420, PubMed:29703751). It acts
CC by partitioning into the membrane and perturbing the interface between
CC the channel and the lipid bilayer without necessarily being in physical
CC contact with the channel. It inhibits atrial fibrillation as well as
CC the membrane motor of outer hair cells at low doses. It also binds to
CC the voltage sensor of voltage-gated potassium channels from the
CC archaebacterium Aeropyrum pernix (KvAP) without affecting channel
CC gating. It shows also a low inhibition on a large spectra of sodium
CC channels (Nav1.1/SCN1A, Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.4/SCN4A,
CC Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A) (IC(50)=7.4-14 uM), and
CC potassium channels Kv11.1/KCNH2 and Kv11.2/KCNH6 (IC(50)=11 uM for
CC both) (PubMed:19955179, PubMed:29703751). It exhibits antimicrobial
CC activities against the Gram-positive bacteria B.subtilis (MIC=0.5 uM),
CC S.aureus (MIC=2-4 uM), and S.epidermidis (MIC=4-8 uM), and Gram-
CC negative bacteria S.typhimurium (MIC=32.64 uM), P.aeruginosa (MIC=8-16
CC uM), and E.coli (MIC=8-16 uM). {ECO:0000269|PubMed:10779316,
CC ECO:0000269|PubMed:11343101, ECO:0000269|PubMed:15241420,
CC ECO:0000269|PubMed:15287735, ECO:0000269|PubMed:16376854,
CC ECO:0000269|PubMed:16797839, ECO:0000269|PubMed:17384064,
CC ECO:0000269|PubMed:17573432, ECO:0000269|PubMed:19955179,
CC ECO:0000269|PubMed:29703751}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10779316}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:10779316}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin. {ECO:0000269|Ref.18}.
CC -!- MASS SPECTROMETRY: Mass=4093.9; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:10779316};
CC -!- MASS SPECTROMETRY: Mass=4092.96; Method=Unknown;
CC Evidence={ECO:0000269|PubMed:12082099};
CC -!- MISCELLANEOUS: This toxin does not inhibit potassium channels
CC Kv1.1/KCNA1, Kv1.4/KCNA4 and Kv11.3/KCNH7 (IC(50)=53->85 uM)
CC (PubMed:19955179). {ECO:0000269|PubMed:19955179}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 52 (MTx4)
CC subfamily. {ECO:0000305}.
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DR EMBL; AY316118; AAP79435.1; -; mRNA.
DR PIR; A59371; A59371.
DR PDB; 1LU8; NMR; -; A=47-80.
DR PDB; 1TYK; NMR; -; A=47-80.
DR PDBsum; 1LU8; -.
DR PDBsum; 1TYK; -.
DR AlphaFoldDB; Q7YT39; -.
DR SMR; Q7YT39; -.
DR TCDB; 8.B.3.1.9; the huwentoxin-1 (huwentoxin-1) family.
DR ArachnoServer; AS000068; M-theraphotoxin-Gr1a.
DR EvolutionaryTrace; Q7YT39; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Antibiotic; Antimicrobial;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Knottin; Lipid-binding; Potassium channel impairing toxin; Secreted;
KW Signal; Toxin; Voltage-gated potassium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..46
FT /evidence="ECO:0000269|PubMed:10779316,
FT ECO:0000269|PubMed:12082099, ECO:0000269|PubMed:19955179,
FT ECO:0000269|Ref.5"
FT /id="PRO_0000035575"
FT CHAIN 47..80
FT /note="M-theraphotoxin-Gr1a"
FT /evidence="ECO:0000269|PubMed:10779316,
FT ECO:0000269|PubMed:12082099, ECO:0000269|PubMed:19955179,
FT ECO:0000269|Ref.5"
FT /id="PRO_0000035576"
FT MOD_RES 80
FT /note="Phenylalanine amide"
FT /evidence="ECO:0000269|PubMed:12082099,
FT ECO:0000269|PubMed:19955179, ECO:0000305|PubMed:14559077"
FT DISULFID 48..63
FT /evidence="ECO:0000269|PubMed:12082099, ECO:0000269|Ref.18,
FT ECO:0000312|PDB:1LU8, ECO:0000312|PDB:1TYK"
FT DISULFID 55..69
FT /evidence="ECO:0000269|PubMed:12082099, ECO:0000269|Ref.18,
FT ECO:0000312|PDB:1LU8, ECO:0000312|PDB:1TYK"
FT DISULFID 62..76
FT /evidence="ECO:0000269|PubMed:12082099, ECO:0000269|Ref.18,
FT ECO:0000312|PDB:1LU8, ECO:0000312|PDB:1TYK"
FT CONFLICT 80
FT /note="F -> S (in Ref. 3; AA sequence and 5; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 51..54
FT /evidence="ECO:0007829|PDB:1TYK"
FT TURN 57..59
FT /evidence="ECO:0007829|PDB:1LU8"
FT STRAND 64..70
FT /evidence="ECO:0007829|PDB:1LU8"
FT TURN 71..74
FT /evidence="ECO:0007829|PDB:1LU8"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:1LU8"
SQ SEQUENCE 82 AA; 9400 MW; 1F92937F1D5DF979 CRC64;
MKTSVVFVIA GLALLSVVCY ASELKEQSSV NEVLSTIFHF EQPEERGCLE FWWKCNPNDD
KCCRPKLKCS KLFKLCNFSF GK
