KA156_TITDI
ID KA156_TITDI Reviewed; 61 AA.
AC P84777; C9X4J2;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 2.
DT 25-MAY-2022, entry version 50.
DE RecName: Full=Potassium channel toxin alpha-KTx 15.6 {ECO:0000303|PubMed:15369825};
DE AltName: Full=Discrepin {ECO:0000303|PubMed:15369825};
DE Flags: Precursor;
OS Tityus discrepans (Venezuelan scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Buthida; Buthoidea; Buthidae; Tityus.
OX NCBI_TaxID=57059;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=19470401; DOI=10.1016/j.biochi.2009.05.005;
RA D'Suze G., Schwartz E.F., Garcia-Gomez B.I., Sevcik C., Possani L.D.;
RT "Molecular cloning and nucleotide sequence analysis of genes from a cDNA
RT library of the scorpion Tityus discrepans.";
RL Biochimie 91:1010-1019(2009).
RN [2]
RP PROTEIN SEQUENCE OF 24-61, FUNCTION, SUBCELLULAR LOCATION, PYROGLUTAMATE
RP FORMATION AT GLN-24, AND NOMENCLATURE.
RC TISSUE=Venom;
RX PubMed=15369825; DOI=10.1016/j.abb.2004.07.010;
RA D'Suze G., Batista C.V.F., Frau A., Murgia A.R., Zamudio F.Z., Sevcik C.,
RA Possani L.D., Prestipino G.;
RT "Discrepin, a new peptide of the sub-family alpha-ktx15, isolated from the
RT scorpion Tityus discrepans irreversibly blocks K+ -channels (IA currents)
RT of cerebellum granular cells.";
RL Arch. Biochem. Biophys. 430:256-263(2004).
RN [3]
RP PROTEIN SEQUENCE OF 24-33, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=16705749; DOI=10.1002/pmic.200500525;
RA Batista C.V.F., D'Suze G., Gomez-Lagunas F., Zamudio F.Z., Encarnacion S.,
RA Sevcik C., Possani L.D.;
RT "Proteomic analysis of Tityus discrepans scorpion venom and amino acid
RT sequence of novel toxins.";
RL Proteomics 6:3718-3727(2006).
RN [4]
RP MUTAGENESIS OF VAL-29; ILE-42; ASP-43; ARG-44 AND THR-58, AND SYNTHESIS OF
RP 24-61.
RX PubMed=18280256; DOI=10.1016/j.bbagen.2008.01.012;
RA Romeo S., Corzo G., Vasile A., Satake H., Prestipino G., Possani L.D.;
RT "A positive charge at the N-terminal segment of discrepin increases the
RT blocking effect of K+ channels responsible for the IA currents in
RT cerebellum granular cells.";
RL Biochim. Biophys. Acta 1780:750-755(2008).
RN [5]
RP MUTAGENESIS OF VAL-29; ILE-42; ASP-43 AND ARG-44.
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 [6]
RP FUNCTION, AND SYNTHESIS OF 24-61.
RX PubMed=29483648; DOI=10.1038/s41594-018-0033-9;
RA Correnti C.E., Gewe M.M., Mehlin C., Bandaranayake A.D., Johnsen W.A.,
RA Rupert P.B., Brusniak M.Y., Clarke M., Burke S.E., De Van Der Schueren W.,
RA Pilat K., Turnbaugh S.M., May D., Watson A., Chan M.K., Bahl C.D.,
RA Olson J.M., Strong R.K.;
RT "Screening, large-scale production and structure-based classification of
RT cystine-dense peptides.";
RL Nat. Struct. Mol. Biol. 25:270-278(2018).
RN [7]
RP STRUCTURE BY NMR OF 24-61, DISULFIDE BONDS, SYNTHESIS OF 24-61, MUTAGENESIS
RP OF THR-58, AND PYROGLUTAMATE FORMATION AT GLN-24.
RC TISSUE=Venom;
RX PubMed=16460026; DOI=10.1021/bi0519248;
RA Prochnicka-Chalufour A., Corzo G., Satake H., Martin-Eauclaire M.-F.,
RA Murgia A.R., Prestipino G., D'Suze G., Possani L.D., Delepierre M.;
RT "Solution structure of discrepin, a new K+-channel blocking peptide from
RT the alpha-KTx15 subfamily.";
RL Biochemistry 45:1795-1804(2006).
CC -!- FUNCTION: Irreversibly blocks the A-type voltage-gated potassium
CC channels in rat cerebellum granular cells (190 nM induce 50% inhibitory
CC effect) (IC(50)=190 nM) (PubMed:15369825, PubMed:18280256). Also weakly
CC inhibits Kv1.2/KCNA2 and Kv1.3/KCNA3 (PubMed:29483648).
CC {ECO:0000269|PubMed:15369825, ECO:0000269|PubMed:18280256,
CC ECO:0000269|PubMed:29483648}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15369825}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:15369825}.
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:16460026}.
CC -!- MASS SPECTROMETRY: Mass=4177; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:16705749};
CC -!- MISCELLANEOUS: Does not block ERG1/Kv11.1/KCNH2 currents.
CC {ECO:0000269|PubMed:18687312}.
CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Potassium
CC channel inhibitor family. Alpha-KTx 15 subfamily. {ECO:0000305}.
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DR EMBL; FN392270; CAY61912.1; -; mRNA.
DR PDB; 2AXK; NMR; -; A=25-61.
DR PDBsum; 2AXK; -.
DR AlphaFoldDB; P84777; -.
DR BMRB; P84777; -.
DR SMR; P84777; -.
DR TCDB; 8.B.8.1.1; the Alpha-ktx15 scorpion toxin (Alpha-ktx15) family.
DR PRIDE; P84777; -.
DR EvolutionaryTrace; P84777; -.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0019870; F:potassium channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0044477; P:envenomation resulting in negative regulation of platelet aggregation in another organism; IDA:CACAO.
DR GO; GO:0044361; P:negative regulation of voltage-gated potassium channel activity in another organism; IDA:UniProtKB.
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 SUPFAM; SSF57095; SSF57095; 1.
DR PROSITE; PS01138; SCORP_SHORT_TOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Neurotoxin; Potassium channel impairing toxin;
KW Pyrrolidone carboxylic acid; Secreted; Signal; Toxin;
KW Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..23
FT /evidence="ECO:0000269|PubMed:15369825"
FT CHAIN 24..61
FT /note="Potassium channel toxin alpha-KTx 15.6"
FT /evidence="ECO:0000269|PubMed:15369825"
FT /id="PRO_0000224192"
FT SITE 51
FT /note="Basic residue of the functional dyad"
FT /evidence="ECO:0000250"
FT SITE 60
FT /note="Aromatic residue of the functional dyad"
FT /evidence="ECO:0000250"
FT MOD_RES 24
FT /note="Pyrrolidone carboxylic acid"
FT /evidence="ECO:0000269|PubMed:15369825,
FT ECO:0000269|PubMed:16460026"
FT DISULFID 31..52
FT /evidence="ECO:0000269|PubMed:16460026,
FT ECO:0000312|PDB:2AXK"
FT DISULFID 37..57
FT /evidence="ECO:0000269|PubMed:16460026,
FT ECO:0000312|PDB:2AXK"
FT DISULFID 41..59
FT /evidence="ECO:0000269|PubMed:16460026,
FT ECO:0000312|PDB:2AXK"
FT MUTAGEN 29
FT /note="V->K: Large increase in blocking A-type potassium
FT currents (IC(50)=51 nM) (keeps irreversible activity). No
FT change in activity towards hERG currents."
FT /evidence="ECO:0000269|PubMed:18280256,
FT ECO:0000269|PubMed:18687312"
FT MUTAGEN 42
FT /note="I->R: Decrease in blocking A-type potassium currents
FT (IC(50)=335 nM). Decrease in blocking A-type potassium
FT currents (IC(50)=235 nM); when associated with K-43.
FT Decrease in blocking A-type potassium currents (IC(50)=335
FT nM). Large decrease in blocking A-type potassium currents
FT (IC(50)=764 nM); when associated with K-43 and V-44. Blocks
FT hERG currents by 18.5% at 2.4 uM. No change in activity
FT towards hERG currents; when associated with K-43. Blocks
FT hERG currents with an IC(50)=3.5 uM; when associated with
FT K-43 and V-44."
FT /evidence="ECO:0000269|PubMed:18280256,
FT ECO:0000269|PubMed:18687312"
FT MUTAGEN 43
FT /note="D->K: Increase in blocking A-type potassium currents
FT (IC(50)=96 nM). Decrease in blocking A-type potassium
FT currents (IC(50)=335 nM). Decrease in blocking A-type
FT potassium currents (IC(50)=235 nM); when associated with R-
FT 42. Large decrease in blocking A-type potassium currents
FT (IC(50)=764 nM); when associated with R-42 and V-44. Blocks
FT hERG currents by 20.2% at 2.4 uM. No change in activity
FT towards hERG currents; when associated with R-42. Blocks
FT hERG currents with an IC(50)=3.5 uM; when associated with
FT R-42 and V-44."
FT /evidence="ECO:0000269|PubMed:18280256,
FT ECO:0000269|PubMed:18687312"
FT MUTAGEN 44
FT /note="R->V: Large decrease in blocking A-type potassium
FT currents (IC(50)=764 nM); when associated with R-42 and K-
FT 43. Blocks hERG currents with an IC(50)=3.5 uM; when
FT associated with R-42 and K-43."
FT /evidence="ECO:0000269|PubMed:18280256,
FT ECO:0000269|PubMed:18687312"
FT MUTAGEN 58
FT /note="T->V: Decrease in blocking A-type potassium currents
FT (IC(50)=261 nM)."
FT /evidence="ECO:0000269|PubMed:18280256"
FT STRAND 25..30
FT /evidence="ECO:0007829|PDB:2AXK"
FT HELIX 34..44
FT /evidence="ECO:0007829|PDB:2AXK"
FT STRAND 50..59
FT /evidence="ECO:0007829|PDB:2AXK"
SQ SEQUENCE 61 AA; 6787 MW; CE0F426D6B00A494 CRC64;
MKAFYGMLVI FILCSTCYIS VDSQIDTNVK CSGSSKCVKI CIDRYNTRGA KCINGRCTCY
P
