H4A01_CYRHA
ID H4A01_CYRHA Reviewed; 86 AA.
AC D2Y232; P83471;
DT 02-NOV-2010, integrated into UniProtKB/Swiss-Prot.
DT 02-MAR-2010, sequence version 1.
DT 25-MAY-2022, entry version 38.
DE RecName: Full=Mu-theraphotoxin-Hhn1b 1 {ECO:0000305};
DE Short=Mu-TRTX-Hhn1b {ECO:0000305};
DE AltName: Full=Hainantoxin-4 {ECO:0000305};
DE AltName: Full=Hainantoxin-IV {ECO:0000303|PubMed:12098779, ECO:0000303|PubMed:12518233, ECO:0000303|PubMed:12827284, ECO:0000303|PubMed:14512091, ECO:0000303|PubMed:15201273, ECO:0000303|PubMed:15859335, ECO:0000303|PubMed:20192277};
DE Short=HnTx-IV {ECO:0000303|PubMed:12518233, ECO:0000303|PubMed:12827284, ECO:0000303|PubMed:15201273, ECO:0000303|PubMed:15859335, ECO:0000303|PubMed:20192277, ECO:0000303|PubMed:29703751};
DE AltName: Full=Peptide F8-18.88;
DE Flags: Precursor;
OS Cyriopagopus hainanus (Chinese bird spider) (Haplopelma hainanum).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Haplopelma.
OX NCBI_TaxID=209901;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], PROTEIN SEQUENCE OF 50-84, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Venom, and Venom gland;
RX PubMed=20192277; DOI=10.1021/pr1000016;
RA Tang X., Zhang Y., Hu W., Xu D., Tao H., Yang X., Li Y., Jiang L.,
RA Liang S.;
RT "Molecular diversification of peptide toxins from the tarantula Haplopelma
RT hainanum (Ornithoctonus hainana) venom based on transcriptomic, peptidomic,
RT and genomic analyses.";
RL J. Proteome Res. 9:2550-2564(2010).
RN [2]
RP PROTEIN SEQUENCE OF 50-84, FUNCTION, TOXIN TARGET, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, MASS SPECTROMETRY, TOXIC DOSE, AND DISULFIDE BONDS.
RX PubMed=12827284; DOI=10.1007/s00018-003-2354-x;
RA Liu Z.-H., Dai J., Chen Z., Hu W., Xiao Y., Liang S.-P.;
RT "Isolation and characterization of hainantoxin-IV, a novel antagonist of
RT tetrodotoxin-sensitive sodium channels from the Chinese bird spider
RT Selenocosmia hainana.";
RL Cell. Mol. Life Sci. 60:972-978(2003).
RN [3]
RP PROTEIN SEQUENCE OF 50-84, FUNCTION, TOXIN TARGET, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, AND AMIDATION AT ILE-84.
RC TISSUE=Venom;
RX PubMed=14512091; DOI=10.1016/s0014-2999(03)02190-3;
RA Xiao Y., Liang S.;
RT "Inhibition of neuronal tetrodotoxin-sensitive Na+ channels by two spider
RT toxins: hainantoxin-III and hainantoxin-IV.";
RL Eur. J. Pharmacol. 477:1-7(2003).
RN [4]
RP FUNCTION.
RX PubMed=12518233;
RA Xiao Y.-C., Liang S.-P.;
RT "Inhibition of sodium channels in rat dorsal root ganglion neurons by
RT Hainantoxin-IV, a novel spider toxin.";
RL Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao 35:82-85(2003).
RN [5]
RP SYNTHESIS.
RX PubMed=12098779;
RA Liu Z.-H., Chen P., Liang S.-P.;
RT "Synthesis and oxidative refolding of hainantoxin-IV.";
RL Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao 34:516-519(2002).
RN [6]
RP SYNTHESIS, AND MUTAGENESIS OF SER-61 AND ARG-78.
RX PubMed=15859335;
RA Xu X., Xiong X., Li D.L., Xiao Y.C., Wang X.C., Liang S.P.;
RT "Solid-phase synthesis and biological characterization of S12A-HNTX-IV and
RT R29A-HNTX-IV: two mutants of hainantoxin-IV.";
RL Sheng Wu Gong Cheng Xue Bao 21:92-96(2005).
RN [7]
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 [8]
RP STRUCTURE BY NMR OF 50-84, DISULFIDE BONDS, AMIDATION AT ILE-84, AND
RP MUTAGENESIS OF SER-61; ARG-75; LYS-76 AND ARG-78.
RX PubMed=15201273; DOI=10.1074/jbc.m405765200;
RA Li D., Xiao Y., Xu X., Xiong X., Lu S., Liu Z., Zhu Q., Wang M., Gu X.,
RA Liang S.;
RT "Structure-activity relationships of hainantoxin-IV and structure
RT determination of active and inactive sodium channel blockers.";
RL J. Biol. Chem. 279:37734-37740(2004).
CC -!- FUNCTION: Neurotoxin that selectively inhibits neuronal tetrodotoxin-
CC sensitive voltage-gated sodium channels (Nav) (IC(50)=44.6 nM)
CC (PubMed:14512091, PubMed:12518233). It is active on Nav1.2/SCN2A
CC (IC(50)=22.4 nM), Nav1.6/SCN8A (IC(50)=50.1 nM) and Nav1.7/SCN9A
CC (IC(50)=48.9 nM) (PubMed:29703751). It shows low affinity for lipid
CC bilayers (PubMed:29703751). {ECO:0000269|PubMed:12518233,
CC ECO:0000269|PubMed:12827284, ECO:0000269|PubMed:14512091,
CC ECO:0000269|PubMed:29703751}.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12827284,
CC ECO:0000269|PubMed:14512091}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000269|PubMed:12827284, ECO:0000269|PubMed:14512091}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:15201273}.
CC -!- MASS SPECTROMETRY: Mass=3988.58; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:12827284};
CC -!- TOXIC DOSE: LD(50) is 0.2 +-0.07 mg/kg by intraperitoneal injection
CC into mice. {ECO:0000269|PubMed:12827284}.
CC -!- MISCELLANEOUS: It does not affect tetrodotoxin-resistant voltage-gated
CC sodium channels or calcium channels. {ECO:0000269|PubMed:12518233,
CC ECO:0000269|PubMed:14512091}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 22 (Htx-4)
CC subfamily. {ECO:0000305}.
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DR EMBL; GU292909; ADB56725.1; -; mRNA.
DR PDB; 1NIY; NMR; -; A=50-84.
DR PDB; 1RYG; NMR; -; A=50-84.
DR PDB; 1RYV; NMR; -; A=50-84.
DR PDBsum; 1NIY; -.
DR PDBsum; 1RYG; -.
DR PDBsum; 1RYV; -.
DR AlphaFoldDB; D2Y232; -.
DR BMRB; D2Y232; -.
DR SMR; D2Y232; -.
DR ArachnoServer; AS000340; mu-theraphotoxin-Hhn1b.
DR EvolutionaryTrace; D2Y232; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR011696; Huwentoxin-1.
DR InterPro; IPR013140; Huwentoxin_CS1.
DR Pfam; PF07740; Toxin_12; 1.
DR PROSITE; PS60021; HWTX_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Presynaptic neurotoxin;
KW Secreted; Signal; Toxin; Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..49
FT /evidence="ECO:0000269|PubMed:12827284,
FT ECO:0000269|PubMed:14512091, ECO:0000269|PubMed:20192277"
FT /id="PRO_0000400566"
FT PEPTIDE 50..84
FT /note="Mu-theraphotoxin-Hhn1b 1"
FT /evidence="ECO:0000269|PubMed:12827284,
FT ECO:0000269|PubMed:14512091, ECO:0000269|PubMed:20192277"
FT /id="PRO_0000400567"
FT SITE 76
FT /note="Interacts with channel"
FT SITE 78
FT /note="Interacts with channel"
FT MOD_RES 84
FT /note="Isoleucine amide"
FT /evidence="ECO:0000269|PubMed:14512091,
FT ECO:0000269|PubMed:15201273"
FT DISULFID 51..66
FT /evidence="ECO:0000269|PubMed:15201273,
FT ECO:0000312|PDB:1NIY, ECO:0000312|PDB:1RYG,
FT ECO:0000312|PDB:1RYV"
FT DISULFID 58..73
FT /evidence="ECO:0000269|PubMed:15201273,
FT ECO:0000312|PDB:1NIY, ECO:0000312|PDB:1RYG,
FT ECO:0000312|PDB:1RYV"
FT DISULFID 65..80
FT /evidence="ECO:0000269|PubMed:15201273,
FT ECO:0000312|PDB:1NIY, ECO:0000312|PDB:1RYG,
FT ECO:0000312|PDB:1RYV"
FT MUTAGEN 61
FT /note="S->A: No important change in activity."
FT /evidence="ECO:0000269|PubMed:15201273,
FT ECO:0000269|PubMed:15859335"
FT MUTAGEN 75
FT /note="R->A: No important change in activity."
FT /evidence="ECO:0000269|PubMed:15201273"
FT MUTAGEN 76
FT /note="K->A: Important reduction in activity, without
FT change of toxin conformation."
FT /evidence="ECO:0000269|PubMed:15201273"
FT MUTAGEN 78
FT /note="R->A: Important reduction in activity, without
FT change of toxin conformation."
FT /evidence="ECO:0000269|PubMed:15201273,
FT ECO:0000269|PubMed:15859335"
FT CONFLICT 61..64
FT /note="SNDQ -> DQSN (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT TURN 60..62
FT /evidence="ECO:0007829|PDB:1NIY"
FT TURN 67..70
FT /evidence="ECO:0007829|PDB:1NIY"
FT STRAND 71..73
FT /evidence="ECO:0007829|PDB:1NIY"
FT STRAND 75..77
FT /evidence="ECO:0007829|PDB:1NIY"
FT STRAND 79..82
FT /evidence="ECO:0007829|PDB:1NIY"
SQ SEQUENCE 86 AA; 9505 MW; 88497767C83CB6DD CRC64;
MKASMFLALA GLALLFVVCY ASESEEKEFS NELLSSVLAV DDNSKGEERE CLGFGKGCNP
SNDQCCKSSN LVCSRKHRWC KYEIGK
