KKX51_HETLA
ID KKX51_HETLA Reviewed; 72 AA.
AC P0DJ41;
DT 18-APR-2012, integrated into UniProtKB/Swiss-Prot.
DT 18-APR-2012, sequence version 1.
DT 25-MAY-2022, entry version 27.
DE RecName: Full=Potassium channel toxin kappa-KTx 5.1 {ECO:0000303|PubMed:22305749};
DE AltName: Full=HelaTx1 {ECO:0000303|PubMed:22305749};
DE Flags: Precursor;
OS Heterometrus laoticus (Thai giant scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Iurida; Scorpionoidea; Scorpionidae; Heterometrinae;
OC Heterometrus.
OX NCBI_TaxID=217256;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 46-70, FUNCTION, DISULFIDE
RP BONDS, AMIDATION AT HIS-70, SYNTHESIS OF 46-70, MASS SPECTROMETRY,
RP SUBCELLULAR LOCATION, AND NOMENCLATURE.
RC TISSUE=Venom, and Venom gland;
RX PubMed=22305749; DOI=10.1016/j.bcp.2012.01.021;
RA Vandendriessche T., Kopljar I., Jenkins D.P., Diego-Garcia E.,
RA Abdel-Mottaleb Y., Vermassen E., Clynen E., Schoofs L., Wulff H.,
RA Snyders D., Tytgat J.;
RT "Purification, molecular cloning and functional characterization of HelaTx1
RT (Heterometrus laoticus): the first member of a new kappa-KTX subfamily.";
RL Biochem. Pharmacol. 83:1307-1317(2012).
RN [2]
RP FUNCTION, SYNTHESIS OF 46-64, AND MUTAGENESIS OF SER-46; ARG-55 AND
RP 65-ASN--HIS-70.
RX PubMed=26724500; DOI=10.1016/j.toxicon.2015.12.014;
RA Peigneur S., Esaki N., Yamaguchi Y., Tytgat J., Sato K.;
RT "Effects of deletion and insertion of amino acids on the activity of
RT HelaTx1, a scorpion toxin on potassium channels.";
RL Toxicon 111:1-5(2016).
RN [3]
RP FUNCTION, MASS SPECTROMETRY, AMIDATION AT HIS-70, AND SYNTHESIS OF 46-70.
RC TISSUE=Venom;
RX PubMed=31276191; DOI=10.1002/1873-3468.13530;
RA Kasheverov I.E., Oparin P.B., Zhmak M.N., Egorova N.S., Ivanov I.A.,
RA Gigolaev A.M., Nekrasova O.V., Serebryakova M.V., Kudryavtsev D.S.,
RA Prokopev N.A., Hoang A.N., Tsetlin V.I., Vassilevski A.A., Utkin Y.N.;
RT "Scorpion toxins interact with nicotinic acetylcholine receptors.";
RL FEBS Lett. 593:2779-2789(2019).
RN [4]
RP STRUCTURE BY NMR OF 46-70, SYNTHESIS OF 46-64, AND MUTAGENESIS OF SER-46;
RP LYS-48; LYS-49; GLY-53; SER-54; ARG-55; ARG-56; LYS-58; LYS-59 AND LYS-63.
RX PubMed=32172732; DOI=10.5483/bmbrep.2020.53.5.256;
RA Park B.G., Peigneur S., Esaki N., Yamaguchi Y., Ryu J.H., Tytgat J.,
RA Kim J.I., Sato K.;
RT "Solution structure and functional analysis of HelaTx1: the first toxin
RT member of the kappa-KTx5 subfamily.";
RL BMB Rep. 53:260-265(2020).
CC -!- FUNCTION: Weak blocker of potassium channels Kv1.1/KCNA1 (IC(50)=578.5
CC nM-9.9 uM) and Kv1.6/KCNA6 (~60% block at 30 uM of toxin)
CC (PubMed:22305749, PubMed:26724500). Acts by binding to the pore and
CC occluding it (PubMed:22305749). Has a voltage-dependent mode of action,
CC which can be explained by a high content of basic residues causing
CC repulsions at higher membrane voltages (PubMed:22305749). Shows a weak
CC interaction with muscle-type nicotinic acetylcholine receptors (nAChR),
CC since it inhibits alpha-bungarotoxin binding to muscle-type nAChR from
CC T.californica (IC(50)=1.4 uM) (PubMed:31276191). This suggests it
CC probably weakly inhibits muscle nAChR (PubMed:31276191). The mode of
CC binding to potassium channels of this toxin differs from its homologs
CC (including HefuTx1), since it lacks the key aromatic residue of the
CC functionnal dyad. In contrast, its functionally important site is
CC composed of a number of basic residues (PubMed:32172732).
CC {ECO:0000269|PubMed:22305749, ECO:0000269|PubMed:31276191,
CC ECO:0000269|PubMed:32172732}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:22305749}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:22305749}.
CC -!- DOMAIN: Has the structural arrangement of two alpha-helices stabilized
CC by disulfide bonds (CSalpha/alpha 2(S-S)).
CC {ECO:0000269|PubMed:32172732, ECO:0000305|PubMed:22305749}.
CC -!- MASS SPECTROMETRY: Mass=2915.34; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:22305749};
CC -!- MASS SPECTROMETRY: Mass=2915.4; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:31276191};
CC -!- MISCELLANEOUS: Does not block or very poorly blocks Kv1.2/KCNA2,
CC Kv1.3/KCNA3 (20%), Kv1.4/KCNA4 (13%), Kv1.5/KCNA5, Kv1.8/KCNA10,
CC Kv2.1/KCNB1, Kv3.1/KCNC1, Kv4.2/KCND2, KCa2.3/KCNN3, KCa3.1/KCNN4
CC (PubMed:22305749). May not inhibit neuronal human alpha-7 nAChR, since
CC it does not inhibit alpha-7 alpha-bungarotoxin binding (IC(50)=64 uM)
CC (PubMed:31276191). {ECO:0000269|PubMed:22305749,
CC ECO:0000269|PubMed:31276191}.
CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Potassium
CC channel inhibitor kappa-KTx family. Kappa-KTx 5 subfamily.
CC {ECO:0000305}.
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DR EMBL; JN872634; AFB73757.1; -; mRNA.
DR PDB; 2NDD; NMR; -; A=46-70.
DR PDBsum; 2NDD; -.
DR AlphaFoldDB; P0DJ41; -.
DR BMRB; P0DJ41; -.
DR SMR; P0DJ41; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0015459; F:potassium 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; Acetylcholine receptor inhibiting toxin; Amidation;
KW Cleavage on pair of basic residues; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Neurotoxin;
KW Postsynaptic neurotoxin; Potassium channel impairing toxin; Secreted;
KW Signal; Toxin; Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT PROPEP 24..43
FT /evidence="ECO:0000305|PubMed:22305749"
FT /id="PRO_0000416812"
FT PEPTIDE 46..70
FT /note="Potassium channel toxin kappa-KTx 5.1"
FT /evidence="ECO:0000269|PubMed:22305749"
FT /id="PRO_0000416813"
FT SITE 48
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 49
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 53
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 55
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 56
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 58
FT /note="Key residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 59
FT /note="Key residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT SITE 63
FT /note="Important residue for potassium channel Kv1.1/KCNA1
FT inhibition"
FT /evidence="ECO:0000269|PubMed:32172732"
FT MOD_RES 70
FT /note="Histidine amide"
FT /evidence="ECO:0000269|PubMed:22305749"
FT DISULFID 47..64
FT /evidence="ECO:0000269|PubMed:22305749,
FT ECO:0000269|PubMed:32172732, ECO:0007744|PDB:2NDD"
FT DISULFID 51..60
FT /evidence="ECO:0000269|PubMed:22305749,
FT ECO:0000269|PubMed:32172732, ECO:0007744|PDB:2NDD"
FT MUTAGEN 46
FT /note="S->A: Slight increase in inhibitory potency towards
FT Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 46
FT /note="Missing: In HelaTx1(2-19): 6-fold decrease in
FT inhibitory potency towards Kv1.1/KCNA1. In
FT [Ala10a]HelaTx1(2-19): 12-fold decrease in inhibitory
FT potency towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:26724500"
FT MUTAGEN 48
FT /note="K->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 49
FT /note="K->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 53
FT /note="G->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 54
FT /note="S->A: Slight increase in inhibitory potency towards
FT Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 55
FT /note="R->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 55
FT /note="R->RA: In [Ala10a]HelaTx1(1-19): 8-fold decrease in
FT inhibitory potency towards Kv1.1/KCNA1. In
FT [Ala10a]HelaTx1(2-19): 12-fold decrease in inhibitory
FT potency towards Kv1.1/KCNA1."
FT MUTAGEN 56
FT /note="R->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 58
FT /note="K->A: Important decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 59
FT /note="K->A: Important decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 63
FT /note="K->A: Moderate decrease in inhibitory potency
FT towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:32172732"
FT MUTAGEN 65..70
FT /note="Missing: In HelaTx1(1-19): 4-fold decrease in
FT inhibitory potency towards Kv1.1/KCNA1. In HelaTx1(2-19):
FT 6-fold decrease in inhibitory potency towards Kv1.1/KCNA1.
FT In [Ala10a]HelaTx1(1-19): 8-fold decrease in inhibitory
FT potency towards Kv1.1/KCNA1. In [Ala10a]HelaTx1(2-19): 12-
FT fold decrease in inhibitory potency towards Kv1.1/KCNA1."
FT /evidence="ECO:0000269|PubMed:26724500"
FT TURN 49..51
FT /evidence="ECO:0007829|PDB:2NDD"
FT HELIX 58..67
FT /evidence="ECO:0007829|PDB:2NDD"
SQ SEQUENCE 72 AA; 8380 MW; C66AC7567D948795 CRC64;
MKLLPLLFVI LIVCAILPDE ASCDQSELER KEENFKDESR EIVKRSCKKE CSGSRRTKKC
MQKCNREHGH GR
