KAX63_HETSP
ID KAX63_HETSP Reviewed; 34 AA.
AC P59867;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2003, sequence version 1.
DT 25-MAY-2022, entry version 84.
DE RecName: Full=Potassium channel toxin alpha-KTx 6.3;
DE AltName: Full=Neurotoxin HsTX1 {ECO:0000303|PubMed:9359871};
OS Heterometrus spinifer (Asia giant forest scorpion) (Malaysian black
OS scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Iurida; Scorpionoidea; Scorpionidae; Heterometrinae;
OC Heterometrus.
OX NCBI_TaxID=118530;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, MASS SPECTROMETRY, DISULFIDE BONDS, AMIDATION
RP AT CYS-34, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=9359871; DOI=10.1042/bj3280321;
RA Lebrun B., Romi-Lebrun R., Martin-Eauclaire M.-F., Yasuda A., Ishiguro M.,
RA Oyama Y., Pongs O., Nakajima T.;
RT "A four-disulphide-bridged toxin, with high affinity towards voltage-gated
RT K+ channels, isolated from Heterometrus spinnifer (Scorpionidae) venom.";
RL Biochem. J. 328:321-327(1997).
RN [2]
RP FUNCTION.
RX PubMed=18687312; DOI=10.1016/j.bcp.2008.07.008;
RA Abdel-Mottaleb Y., Corzo G., Martin-Eauclaire M.F., Satake H., Ceard B.,
RA Peigneur S., Nambaru P., Bougis P.E., Possani L.D., Tytgat J.;
RT "A common 'hot spot' confers hERG blockade activity to alpha-scorpion
RT toxins affecting K+ channels.";
RL Biochem. Pharmacol. 76:805-815(2008).
RN [3]
RP 3D-STRUCTURE MODELING IN COMPLEX WITH KV1.1; KV1.2 AND KV1.3.
RX PubMed=24397610; DOI=10.1021/jp410950h;
RA Rashid M.H., Kuyucak S.;
RT "Free energy simulations of binding of HsTx1 toxin to Kv1 potassium
RT channels: the basis of Kv1.3/Kv1.1 selectivity.";
RL J. Phys. Chem. B 118:707-716(2014).
RN [4]
RP FUNCTION, SYNTHESIS, 3D-STRUCTURE MODELING IN COMPLEX WITH KV1.1 AND KV1.3,
RP MUTAGENESIS OF ARG-14, AND PHARMACEUTICAL.
RX PubMed=24676092; DOI=10.1038/srep04509;
RA Rashid M.H., Huq R., Tanner M.R., Chhabra S., Khoo K.K., Estrada R.,
RA Dhawan V., Chauhan S., Pennington M.W., Beeton C., Kuyucak S., Norton R.S.;
RT "A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a
RT potential therapeutic for autoimmune diseases.";
RL Sci. Rep. 4:4509-4509(2014).
RN [5]
RP FUNCTION, MUTAGENESIS OF ARG-14, PEGYLATION OF MUTANT HSTX1[R14A], AND
RP PHARMACEUTICAL.
RX PubMed=28389388; DOI=10.1016/j.clim.2017.03.014;
RA Tanner M.R., Tajhya R.B., Huq R., Gehrmann E.J., Rodarte K.E., Atik M.A.,
RA Norton R.S., Pennington M.W., Beeton C.;
RT "Prolonged immunomodulation in inflammatory arthritis using the selective
RT Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog.";
RL Clin. Immunol. 180:45-57(2017).
RN [6]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=10631983; DOI=10.1110/ps.8.12.2672;
RA Savarin P., Romi-Lebrun R., Zinn-Justin S., Lebrun B., Nakajima T.,
RA Gilquin B., Menez A.;
RT "Structural and functional consequences of the presence of a fourth
RT disulfide bridge in the scorpion short toxins: solution structure of the
RT potassium channel inhibitor HsTX1.";
RL Protein Sci. 8:2672-2685(1999).
RN [7]
RP STRUCTURE BY NMR OF A MAUROTOXIN-HSTX1 CHIMERA, AND FUNCTION.
RX PubMed=15498765; DOI=10.1074/jbc.m410055200;
RA Regaya I., Beeton C., Ferrat G., Andreotti N., Darbon H., De Waard M.,
RA Sabatier J.M.;
RT "Evidence for domain-specific recognition of SK and Kv channels by MTX and
RT HsTx1 scorpion toxins.";
RL J. Biol. Chem. 279:55690-55696(2004).
RN [8]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=16247791; DOI=10.1002/prot.20681;
RA Carrega L., Mosbah A., Ferrat G., Beeton C., Andreotti N., Mansuelle P.,
RA Darbon H., De Waard M., Sabatier J.M.;
RT "The impact of the fourth disulfide bridge in scorpion toxins of the alpha-
RT KTx6 subfamily.";
RL Proteins 61:1010-1023(2005).
CC -!- FUNCTION: Potently blocks voltage-gated potassium channels Kv1.1/KCNA1
CC (IC(50)=7-11 nM) and Kv1.3/KCNA3 (IC(50)=11-29 pM) (PubMed:9359871,
CC PubMed:24676092, PubMed:15498765). Also mildly blocks intermediate (IK)
CC conductance calcium-activated potassium channels (KCa3.1/KCNN4) and
CC ERG1/Kv11.1/KCNH2 (PubMed:18687312, PubMed:15498765). Shows ability to
CC suppress proliferation of lymphocytes, which are known to be sensitive
CC to Kv1.3/KCNA3 homotetrameric channel block (PubMed:24676092).
CC {ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:18687312,
CC ECO:0000269|PubMed:24676092, ECO:0000269|PubMed:9359871}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9359871}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:9359871}.
CC -!- DOMAIN: Has the structural arrangement of an alpha-helix connected to a
CC beta-sheet by disulfide bonds (CSalpha/beta).
CC {ECO:0000269|PubMed:10631983, ECO:0000269|PubMed:16247791}.
CC -!- DOMAIN: The lower affinity for Kv1.1/KCNA1 is due to HsTX1 inability to
CC come close to the pore domain, which prevents the pore-inserting lysine
CC (Lys-23) from making proper contacts with the tyrosine carbonyls in the
CC selectivity filter of the channel. {ECO:0000305|PubMed:24397610}.
CC -!- PTM: Amidated (PubMed:9359871). The amidated toxin shows 5-fold more
CC affinity for Kv1.3/KCNA3 than the synthetic carboxylated form
CC (PubMed:9359871). {ECO:0000269|PubMed:9359871}.
CC -!- MASS SPECTROMETRY: Mass=3815.63; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:9359871};
CC -!- PHARMACEUTICAL: Some analogs of this peptide are potential candidate
CC for treatment of autoimmune diseases through block of Kv1.3/KCNA3.
CC {ECO:0000305|PubMed:24676092, ECO:0000305|PubMed:28389388}.
CC -!- MISCELLANEOUS: Does not block Kv1.2/KCNA2 potassium channels
CC (PubMed:15498765). Does not induce hemolysis (PubMed:24676092).
CC {ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:24676092}.
CC -!- MISCELLANEOUS: PEGylation of HsTX1[R14A] enhances its circulating half-
CC life in rats, reduces its affinity but not its selectivity for
CC Kv1.3/KCNA3, and dramatically reduces its adsorption to inert surfaces.
CC PEG-HsTX1[R14A] is equipotent to HsTX1[R14A] in preferential inhibition
CC of human and rat CCR7(-) effector memory T lymphocytes (TEM)
CC proliferation, leaving CCR7(+) naive and central memory T cells able to
CC proliferate. It reduces inflammation in an active delayed-type
CC hypersensitivity model and in the pristane-induced arthritis (PIA)
CC model of rheumatoid arthritis (RA). Importantly, a single subcutaneous
CC dose of PEG-HsTX1[R14A] reduces inflammation in PIA for a longer period
CC of time than the non-PEGylated HsTX1[R14A]. Together, these data
CC indicate that HsTX1[R14A] and PEG-HsTX1[R14A] are effective in a model
CC of RA and are therefore potential therapeutics for TEM cell-mediated
CC autoimmune diseases. {ECO:0000269|PubMed:28389388}.
CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Potassium
CC channel inhibitor family. Alpha-KTx 06 subfamily. {ECO:0000305}.
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DR PDB; 1QUZ; NMR; -; A=1-34.
DR PDB; 1WPD; NMR; -; A=7-34.
DR PDB; 1Y2P; NMR; -; A=1-34.
DR PDBsum; 1QUZ; -.
DR PDBsum; 1WPD; -.
DR PDBsum; 1Y2P; -.
DR AlphaFoldDB; P59867; -.
DR BMRB; P59867; -.
DR SMR; P59867; -.
DR EvolutionaryTrace; P59867; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.30.10; -; 1.
DR InterPro; IPR036574; Scorpion_toxin-like_sf.
DR InterPro; IPR001947; Scorpion_toxinS_K_inh.
DR Pfam; PF00451; Toxin_2; 1.
DR PRINTS; PR00286; CHARYBDTOXIN.
DR SUPFAM; SSF57095; SSF57095; 1.
DR PROSITE; PS01138; SCORP_SHORT_TOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation;
KW Calcium-activated potassium channel impairing toxin;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Neurotoxin; Pharmaceutical; Potassium channel impairing toxin; Secreted;
KW Toxin; Voltage-gated potassium channel impairing toxin.
FT PEPTIDE 1..34
FT /note="Potassium channel toxin alpha-KTx 6.3"
FT /evidence="ECO:0000269|PubMed:9359871"
FT /id="PRO_0000044908"
FT SITE 21
FT /note="Important for activity"
FT /evidence="ECO:0000305|PubMed:10631983"
FT SITE 23
FT /note="Critical for activity (is inserted in the pore,
FT pointing downward)"
FT /evidence="ECO:0000305|PubMed:10631983"
FT SITE 25
FT /note="Important for activity"
FT /evidence="ECO:0000305|PubMed:10631983"
FT SITE 26
FT /note="Important for activity"
FT /evidence="ECO:0000305|PubMed:10631983"
FT SITE 33
FT /note="Important for activity"
FT /evidence="ECO:0000305|PubMed:10631983"
FT MOD_RES 34
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:9359871"
FT DISULFID 3..24
FT /evidence="ECO:0000269|PubMed:10631983,
FT ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:16247791,
FT ECO:0000312|PDB:1Y2P, ECO:0007744|PDB:1QUZ"
FT DISULFID 9..29
FT /evidence="ECO:0000269|PubMed:10631983,
FT ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:16247791,
FT ECO:0000312|PDB:1Y2P, ECO:0007744|PDB:1QUZ"
FT DISULFID 13..31
FT /evidence="ECO:0000269|PubMed:10631983,
FT ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:16247791,
FT ECO:0000312|PDB:1Y2P, ECO:0007744|PDB:1QUZ"
FT DISULFID 19..34
FT /evidence="ECO:0000269|PubMed:10631983,
FT ECO:0000269|PubMed:15498765, ECO:0000269|PubMed:16247791,
FT ECO:0007744|PDB:1QUZ"
FT MUTAGEN 14
FT /note="R->A: Increase in selectivity for Kv1.3/KCNA3 over
FT Kv1.1/KCNA1 (>2000-fold more selective). Very weak decrease
FT in inhibition of Kv1.3/KCNA3 and important decrease in
FT inhibition of Kv1.1/KCNA1. No change in ability to suppress
FT lymphocyte proliferation."
FT /evidence="ECO:0000269|PubMed:24676092,
FT ECO:0000269|PubMed:28389388"
FT HELIX 6..9
FT /evidence="ECO:0007829|PDB:1QUZ"
FT HELIX 10..16
FT /evidence="ECO:0007829|PDB:1QUZ"
FT STRAND 18..20
FT /evidence="ECO:0007829|PDB:1Y2P"
FT STRAND 22..27
FT /evidence="ECO:0007829|PDB:1QUZ"
FT STRAND 29..31
FT /evidence="ECO:0007829|PDB:1QUZ"
SQ SEQUENCE 34 AA; 3828 MW; 6078F957A4FDF39A CRC64;
ASCRTPKDCA DPCRKETGCP YGKCMNRKCK CNRC
