BDS2_ANTEL
ID BDS2_ANTEL Reviewed; 42 AA.
AC P61542;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 24-MAY-2004, sequence version 1.
DT 25-MAY-2022, entry version 67.
DE RecName: Full=Pi-actitoxin-Ael2b {ECO:0000303|PubMed:22851929};
DE Short=Pi-AITX-Ael2b {ECO:0000303|PubMed:22851929};
DE AltName: Full=Toxin APETx2 {ECO:0000303|PubMed:15044953};
OS Anthopleura elegantissima (Green aggregating anemone) (Actinia
OS elegantissima).
OC Eukaryota; Metazoa; Cnidaria; Anthozoa; Hexacorallia; Actiniaria;
OC Actiniidae; Anthopleura.
OX NCBI_TaxID=6110;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, MASS SPECTROMETRY, DISULFIDE BONDS, SUBCELLULAR
RP LOCATION, AND 3D-STRUCTURE MODELING.
RX PubMed=15044953; DOI=10.1038/sj.emboj.7600177;
RA Diochot S., Baron A., Rash L.D., Deval E., Escoubas P., Scarzello S.,
RA Salinas M., Lazdunski M.;
RT "A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive
RT channel in sensory neurons.";
RL EMBO J. 23:1516-1525(2004).
RN [2]
RP FUNCTION, AND BIOASSAY.
RX PubMed=18923424; DOI=10.1038/emboj.2008.213;
RA Deval E., Noel J., Lay N., Alloui A., Diochot S., Friend V., Jodar M.,
RA Lazdunski M., Lingueglia E.;
RT "ASIC3, a sensor of acidic and primary inflammatory pain.";
RL EMBO J. 27:3047-3055(2008).
RN [3]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=19306891; DOI=10.1016/j.toxicon.2009.03.014;
RA Jensen J.E., Durek T., Alewood P.F., Adams D.J., King G.F., Rash L.D.;
RT "Chemical synthesis and folding of APETx2, a potent and selective inhibitor
RT of acid sensing ion channel 3.";
RL Toxicon 54:56-61(2009).
RN [4]
RP FUNCTION, MUTAGENESIS OF ARG-17, AND SITE ARG-17.
RX PubMed=20813121; DOI=10.1016/j.toxicon.2010.08.004;
RA Anangi R., Chen C.C., Lin Y.W., Cheng Y.R., Cheng C.H., Chen Y.C.,
RA Chu Y.P., Chuang W.J.;
RT "Expression in Pichia pastoris and characterization of APETx2, a specific
RT inhibitor of acid sensing ion channel 3.";
RL Toxicon 56:1388-1397(2010).
RN [5]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=21943094; DOI=10.1111/j.1476-5381.2011.01674.x;
RA Blanchard M.G., Rash L.D., Kellenberger S.;
RT "Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea
RT anemone toxin APETx2.";
RL Br. J. Pharmacol. 165:2167-2177(2012).
RN [6]
RP FUNCTION.
RX PubMed=22972919; DOI=10.1096/fj.12-218479;
RA Peigneur S., Beress L., Moeller C., Mari F., Forssmann W.G., Tytgat J.;
RT "A natural point mutation changes both target selectivity and mechanism of
RT action of sea anemone toxins.";
RL FASEB J. 26:5141-5151(2012).
RN [7]
RP FUNCTION, MUTAGENESIS OF 1-GLY-THR-2 AND 40-PRO--ASP-42, SYNTHESIS, AND
RP SITES GLY-1 AND THR-2.
RX PubMed=22851922; DOI=10.3390/md10071511;
RA Jensen J.E., Mobli M., Brust A., Alewood P.F., King G.F., Rash L.D.;
RT "Cyclisation increases the stability of the sea anemone peptide APETx2 but
RT decreases its activity at acid-sensing ion channel 3.";
RL Mar. Drugs 10:1511-1527(2012).
RN [8]
RP FUNCTION, MUTAGENESIS OF PHE-15, AND SITE PHE-15.
RX PubMed=22851929; DOI=10.3390/md10071605;
RA Anangi R., Rash L.D., Mobli M., King G.F.;
RT "Functional expression in Escherichia coli of the disulfide-rich sea
RT anemone peptide APETx2, a potent blocker of acid-sensing ion channel 3.";
RL Mar. Drugs 10:1605-1618(2012).
RN [9]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=15987885; DOI=10.1110/ps.051378905;
RA Chagot B., Escoubas P., Diochot S., Bernard C., Lazdunski M., Darbon H.;
RT "Solution structure of APETx2, a specific peptide inhibitor of ASIC3
RT proton-gated channels.";
RL Protein Sci. 14:2003-2010(2005).
RN [10]
RP STRUCTURE BY NMR, FUNCTION, DISULFIDE BOND, SYNTHESIS, AND MUTAGENESIS OF
RP SER-5; ASN-8; LYS-10; TYR-16; ARG-17; ASP-23; ARG-24; ARG-31; TYR-32;
RP PHE-33 AND LEU-34.
RX PubMed=25337890; DOI=10.1021/jm501400p;
RA Jensen J.E., Cristofori-Armstrong B., Anangi R., Rosengren K.J., Lau C.H.,
RA Mobli M., Brust A., Alewood P.F., King G.F., Rash L.D.;
RT "Understanding the molecular basis of toxin promiscuity: the analgesic sea
RT anemone peptide APETx2 interacts with acid-sensing ion channel 3 and hERG
RT channels via overlapping pharmacophores.";
RL J. Med. Chem. 57:9195-9203(2014).
CC -!- FUNCTION: This toxin potently blocks acid-sensing ion channel ASIC3
CC homotrimers and heterotrimers containing ASIC3 (composed with isoforms
CC of ASIC1 and ASIC2) (PubMed:15044953). It also weakly inhibits
CC potassium channels, and sodium channels (PubMed:15044953,
CC PubMed:21943094, PubMed:22972919, PubMed:25337890). On homomeric ASIC3,
CC this protein shows IC(50)=57-87 nM on rat, 37.3 nM on mouse and 175 nM
CC on human channels (PubMed:15044953, PubMed:18923424, PubMed:19306891,
CC PubMed:20813121, PubMed:21943094, PubMed:22851922, PubMed:22851929).
CC The blockade is rapid and reversible (PubMed:15044953). On
CC heterotrimeric forms, the toxin is less potent (IC(50)=117 nM on rat
CC ASIC2b-ASIC3 channel, 900 nM on rat ASIC1b-ASIC3, and 2 uM on rat
CC ASIC1a-ASIC3) (PubMed:15044953). It weakly inhibits Kv3.4/KCNC4
CC potassium channels (3 uM of the toxin inhibits 38% of Kv3.4 current)
CC (PubMed:15044953). It reversibly and voltage-dependently inhibits
CC hKv11.1/KCNH2/ERG1 potassium channels (IC(50)=1.21 uM), inhibiting both
CC peak and tail currents without action on channel inactivation
CC (PubMed:25337890). It weakly inhibits rNav1.2/SCN2A (EC(50)=114 nM),
CC rNav1.6/SCN8A current (17% at 1 uM of the toxin) and Nav1.8/SCN10A
CC (IC(50)=6.6 uM on human channels expressed in oocytes, EC(50)=55 nM on
CC rat channels expressed in oocytes, and 2.6 uM on rat channels in DRG
CC neurons) (PubMed:21943094, PubMed:22972919). It may act on sodium
CC channels by binding at site 1 or close by, when the pore is in an open
CC configuration (PubMed:22972919). In vivo, central injection does not
CC induce neurotoxin symptoms in mice even after 24 hours
CC (PubMed:15044953). However, it abolishes acid-induced pain in rats
CC (PubMed:18923424). {ECO:0000269|PubMed:15044953,
CC ECO:0000269|PubMed:18923424, ECO:0000269|PubMed:19306891,
CC ECO:0000269|PubMed:20813121, ECO:0000269|PubMed:21943094,
CC ECO:0000269|PubMed:22851922, ECO:0000269|PubMed:22851929,
CC ECO:0000269|PubMed:22972919, ECO:0000269|PubMed:25337890}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15044953}.
CC Nematocyst {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=4557.96; Method=MALDI; Note=Monoisotopic mass.;
CC Evidence={ECO:0000269|PubMed:15044953};
CC -!- PHARMACEUTICAL: Is under preclinical studies as a novel analgesic for
CC the treatment of chronic inflammatory pain.
CC {ECO:0000305|PubMed:22851922}.
CC -!- MISCELLANEOUS: This protein does not block rat ASIC1a and ASIC1b (ASIC1
CC isoforms), ASIC2a (ASIC2 isoform), and the heteromeric ASIC2a-ASIC3
CC channels (PubMed:15044953, PubMed:18923424, PubMed:19306891). It also
CC does not inhibit most of voltage-gated potassium channels tested
CC (Kv1.4, Kv2.2, Kv3.1, Kv4.1, Kv4.2, Kv4.3) (PubMed:15044953). It does
CC not inhibit Nav1.3, Nav1.4, Nav1.5 and Nav1.7 (PubMed:22972919). It
CC shows a very weak inhibition on Nav1.6 (17% inhibition by 1 uM of the
CC toxin) (PubMed:22972919). {ECO:0000269|PubMed:15044953,
CC ECO:0000269|PubMed:18923424, ECO:0000269|PubMed:22972919}.
CC -!- SIMILARITY: Belongs to the sea anemone type 3 (BDS) potassium channel
CC toxin family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR PDB; 1WXN; NMR; -; A=1-42.
DR PDB; 2MUB; NMR; -; A=1-42.
DR PDBsum; 1WXN; -.
DR PDBsum; 2MUB; -.
DR AlphaFoldDB; P61542; -.
DR BMRB; P61542; -.
DR SMR; P61542; -.
DR TCDB; 8.B.11.1.2; the sea anemone peptide toxin (apetx) family.
DR EvolutionaryTrace; P61542; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042151; C:nematocyst; 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:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 2.20.20.10; -; 1.
DR InterPro; IPR012414; BDS_K_chnl_tox.
DR InterPro; IPR023355; Myo_ane_neurotoxin_sf.
DR Pfam; PF07936; Defensin_4; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Nematocyst; Pharmaceutical;
KW Potassium channel impairing toxin;
KW Proton-gated sodium channel impairing toxin; Secreted; Toxin;
KW Voltage-gated potassium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT CHAIN 1..42
FT /note="Pi-actitoxin-Ael2b"
FT /evidence="ECO:0000269|PubMed:15044953"
FT /id="PRO_0000221540"
FT REGION 13..14
FT /note="Play an important role in the folding and structural
FT integrity of APETx2"
FT /evidence="ECO:0000269|PubMed:25337890"
FT SITE 1
FT /note="Important in ability to inhibit ASIC3"
FT /evidence="ECO:0000269|PubMed:22851922"
FT SITE 2
FT /note="Important in ability to inhibit ASIC3"
FT /evidence="ECO:0000269|PubMed:22851922"
FT SITE 8
FT /note="Important in ability to inhibit Kv11.1/KCNH2/ERG1"
FT /evidence="ECO:0000269|PubMed:25337890"
FT SITE 15
FT /note="Important in ability to inhibit ASIC3"
FT /evidence="ECO:0000269|PubMed:22851929,
FT ECO:0000305|PubMed:15987885"
FT SITE 16
FT /note="Important in ability to inhibit ASIC3"
FT /evidence="ECO:0000269|PubMed:25337890,
FT ECO:0000305|PubMed:15987885"
FT SITE 17
FT /note="Important in ability to inhibit ASIC3"
FT /evidence="ECO:0000269|PubMed:20813121,
FT ECO:0000269|PubMed:25337890, ECO:0000305|PubMed:15987885"
FT SITE 18
FT /note="Important in ability to inhibit Kv11.1/KCNH2/ERG1"
FT /evidence="ECO:0000269|PubMed:25337890"
FT SITE 24
FT /note="Probably important in ability to inhibit ASIC3"
FT /evidence="ECO:0000305|PubMed:25337890"
FT SITE 31
FT /note="Interacts with ASIC3"
FT /evidence="ECO:0000305|PubMed:15987885"
FT SITE 32
FT /note="Interacts with ASIC3"
FT /evidence="ECO:0000305|PubMed:15987885"
FT SITE 33
FT /note="Important in ability to inhibit both ASIC3 and
FT Kv11.1/KCNH2/ERG1"
FT /evidence="ECO:0000269|PubMed:25337890,
FT ECO:0000305|PubMed:15987885"
FT SITE 34
FT /note="Important in ability to inhibit both ASIC3 and
FT Kv11.1/KCNH2/ERG1"
FT /evidence="ECO:0000269|PubMed:25337890"
FT DISULFID 4..37
FT /evidence="ECO:0000269|PubMed:15044953,
FT ECO:0000269|PubMed:15987885, ECO:0000269|PubMed:25337890,
FT ECO:0000312|PDB:1WXN, ECO:0000312|PDB:2MUB"
FT DISULFID 6..30
FT /evidence="ECO:0000269|PubMed:15044953,
FT ECO:0000269|PubMed:15987885, ECO:0000269|PubMed:25337890,
FT ECO:0000312|PDB:1WXN, ECO:0000312|PDB:2MUB"
FT DISULFID 20..38
FT /evidence="ECO:0000269|PubMed:15044953,
FT ECO:0000269|PubMed:15987885, ECO:0000269|PubMed:25337890,
FT ECO:0000312|PDB:1WXN, ECO:0000312|PDB:2MUB"
FT MUTAGEN 1..2
FT /note="Missing: 300-fold decrease in ability to inhibit
FT rASIC3 and small decrease in ability to inhibit
FT hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:22851922,
FT ECO:0000269|PubMed:25337890"
FT MUTAGEN 3
FT /note="A->P: 4.1-fold decrease in ability to inhibit rASIC3
FT and no change in ability to inhibit hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 5
FT /note="S->A: 2.5-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 8
FT /note="N->A: 1.2-fold increase in ability to inhibit rASIC3
FT and decrease in ability to inhibit hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 10
FT /note="K->A: 1.8-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 15
FT /note="F->A: >100-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:22851929"
FT MUTAGEN 16
FT /note="Y->A,F: Complete loss of ability to inhibit rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 17
FT /note="R->A: 44-fold decrease in ability to inhibit rASIC3
FT and mASIC3."
FT /evidence="ECO:0000269|PubMed:20813121,
FT ECO:0000269|PubMed:25337890"
FT MUTAGEN 17
FT /note="R->E: Complete loss of ability to inhibit rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 18
FT /note="P->A: 3-fold decrease in ability to inhibit rASIC3
FT and decrease in ability to inhibit hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 23
FT /note="D->A: 1.1-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 24
FT /note="R->A,Q: About 25-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 31
FT /note="R->A: 2.1-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 32
FT /note="Y->A: 2.5-fold decrease in ability to inhibit
FT rASIC3, probably due to alterations in the orientation of
FT the side chains of neighboring residues of functional
FT importance. No change in ability to inhibit
FT hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 33
FT /note="F->A: Complete loss of ability to inhibit rASIC3 and
FT hKv11.1/KCNH2/ERG1 (tail current only)."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 34
FT /note="L->A: Complete loss of ability to inhibit rASIC3 and
FT hKv11.1/KCNH2/ERG1."
FT /evidence="ECO:0000269|PubMed:25337890"
FT MUTAGEN 40..42
FT /note="Missing: 18-fold decrease in ability to inhibit
FT rASIC3."
FT /evidence="ECO:0000269|PubMed:22851922"
FT STRAND 3..6
FT /evidence="ECO:0007829|PDB:1WXN"
FT STRAND 9..16
FT /evidence="ECO:0007829|PDB:1WXN"
FT HELIX 22..24
FT /evidence="ECO:0007829|PDB:1WXN"
FT STRAND 28..32
FT /evidence="ECO:0007829|PDB:1WXN"
FT STRAND 35..39
FT /evidence="ECO:0007829|PDB:1WXN"
SQ SEQUENCE 42 AA; 4567 MW; 3E8B26BA8655781D CRC64;
GTACSCGNSK GIYWFYRPSC PTDRGYTGSC RYFLGTCCTP AD
