TXP1_PSACA
ID TXP1_PSACA Reviewed; 40 AA.
AC P60514;
DT 01-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2004, sequence version 1.
DT 25-MAY-2022, entry version 80.
DE RecName: Full=Psalmotoxin-1 {ECO:0000303|PubMed:10829030, ECO:0000303|PubMed:12824480, ECO:0000303|PubMed:15955877, ECO:0000303|PubMed:16505147};
DE AltName: Full=PcTx1 {ECO:0000303|PubMed:10829030, ECO:0000303|PubMed:12824480};
DE AltName: Full=Pi-theraphotoxin-Pc1a {ECO:0000303|PubMed:21825095};
DE Short=Pi-TRTX-Pc1a {ECO:0000303|PubMed:21825095};
OS Psalmopoeus cambridgei (Trinidad chevron tarantula).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Psalmopoeus.
OX NCBI_TaxID=179874;
RN [1]
RP PROTEIN SEQUENCE, SYNTHESIS, FUNCTION, MASS SPECTROMETRY, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Venom;
RX PubMed=10829030; DOI=10.1074/jbc.m003643200;
RA Escoubas P., de Weille J.R., Lecoq A., Diochot S., Waldmann R.,
RA Champigny G., Moinier D., Menez A., Lazdunski M.;
RT "Isolation of a tarantula toxin specific for a class of proton-gated Na+
RT channels.";
RL J. Biol. Chem. 275:25116-25121(2000).
RN [2]
RP FUNCTION.
RX PubMed=15955877; DOI=10.1085/jgp.200509303;
RA Chen X., Kalbacher H., Gruender S.;
RT "The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC)
RT 1a by increasing its apparent H+ affinity.";
RL J. Gen. Physiol. 126:71-79(2005).
RN [3]
RP FUNCTION.
RX PubMed=16505147; DOI=10.1085/jgp.200509409;
RA Chen X., Kalbacher H., Gruender S.;
RT "Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin
RT psalmotoxin 1 is state dependent.";
RL J. Gen. Physiol. 127:267-276(2006).
RN [4]
RP FUNCTION ON CHICKEN ASIC1.
RX PubMed=19185346; DOI=10.1016/j.ceca.2008.12.002;
RA Samways D.S., Harkins A.B., Egan T.M.;
RT "Native and recombinant ASIC1a receptors conduct negligible Ca2+ entry.";
RL Cell Calcium 45:319-325(2009).
RN [5]
RP FUNCTION.
RX PubMed=21036899; DOI=10.1074/jbc.m110.171330;
RA Hoagland E.N., Sherwood T.W., Lee K.G., Walker C.J., Askwith C.C.;
RT "Identification of a calcium permeable human acid-sensing ion channel 1
RT transcript variant.";
RL J. Biol. Chem. 285:41852-41862(2010).
RN [6]
RP FUNCTION.
RX PubMed=21715637; DOI=10.1523/jneurosci.1665-11.2011;
RA Sherwood T.W., Lee K.G., Gormley M.G., Askwith C.C.;
RT "Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and
RT ASIC1a display novel channel properties and contribute to acidosis-induced
RT neuronal death.";
RL J. Neurosci. 31:9723-9734(2011).
RN [7]
RP FUNCTION.
RX PubMed=24262969; DOI=10.4161/chan.26978;
RA Smith R.N., Gonzales E.B.;
RT "Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in
RT chicken acid-sensing ion channel: Implication for simultaneous modulation
RT in ASICs.";
RL Channels 8:49-61(2014).
RN [8]
RP FUNCTION, MUTAGENESIS OF 1-GLU-ASP-2; LYS-6; TRP-7; LYS-8; ARG-28; SER-29;
RP PHE-30; GLU-31; VAL-32; VAL-34; PRO-35; LYS-36; THR-37; PRO-38 AND
RP 38-PRO--THR-40, AND SITES TRP-7; ARG-28; PHE-30.
RX PubMed=26248594; DOI=10.1111/bph.13267;
RA Saez N.J., Deplazes E., Cristofori-Armstrong B., Chassagnon I.R., Lin X.,
RA Mobli M., Mark A.E., Rash L.D., King G.F.;
RT "Molecular dynamics and functional studies define a hot spot of crystal
RT contacts essential for psalmotoxin-1 inhibition of acid-sensing ion channel
RT 1a.";
RL Br. J. Pharmacol. 172:4985-4995(2015).
RN [9]
RP PHARMACEUTICAL.
RX PubMed=26320544; DOI=10.1016/j.neuropharm.2015.08.040;
RA McCarthy C.A., Rash L.D., Chassagnon I.R., King G.F., Widdop R.E.;
RT "PcTx1 affords neuroprotection in a conscious model of stroke in
RT hypertensive rats via selective inhibition of ASIC1a.";
RL Neuropharmacology 99:650-657(2015).
RN [10]
RP FUNCTION.
RX PubMed=27277303; DOI=10.1038/srep27647;
RA Joeres N., Augustinowski K., Neuhof A., Assmann M., Gruender S.;
RT "Functional and pharmacological characterization of two different ASIC1a/2a
RT heteromers reveals their sensitivity to the spider toxin PcTx1.";
RL Sci. Rep. 6:27647-27659(2016).
RN [11]
RP FUNCTION.
RC TISSUE=Venom;
RX PubMed=28320941; DOI=10.1073/pnas.1614728114;
RA Chassagnon I.R., McCarthy C.A., Chin Y.K., Pineda S.S., Keramidas A.,
RA Mobli M., Pham V., De Silva T.M., Lynch J.W., Widdop R.E., Rash L.D.,
RA King G.F.;
RT "Potent neuroprotection after stroke afforded by a double-knot spider-venom
RT peptide that inhibits acid-sensing ion channel 1a.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:3750-3755(2017).
RN [12]
RP REVIEW, AND PHARMACEUTICAL.
RX PubMed=28457973; DOI=10.1016/j.neuropharm.2017.04.042;
RA Cristofori-Armstrong B., Rash L.D.;
RT "Acid-sensing ion channel (ASIC) structure and function: insights from
RT spider, snake and sea anemone venoms.";
RL Neuropharmacology 127:173-184(2017).
RN [13]
RP STRUCTURE BY NMR, DISULFIDE BONDS, AND MASS SPECTROMETRY.
RX PubMed=12824480; DOI=10.1110/ps.0307003;
RA Escoubas P., Bernard C., Lambeau G., Lazdunski M., Darbon H.;
RT "Recombinant production and solution structure of PcTx1, the specific
RT peptide inhibitor of ASIC1a proton-gated cation channels.";
RL Protein Sci. 12:1332-1343(2003).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS), DISULFIDE BONDS, MUTAGENESIS OF
RP HIS-14; TRP-24; LYS-25; ARG-26 AND ARG-27, SITES TRP-24; ARG-26 AND ARG-27,
RP AND 3D-STRUCTURE MODELING OF THE TOXIN IN COMPLEX WITH RAT ASIC1A.
RX PubMed=21825095; DOI=10.1124/mol.111.072207;
RA Saez N.J., Mobli M., Bieri M., Chassagnon I.R., Malde A.K., Gamsjaeger R.,
RA Mark A.E., Gooley P.R., Rash L.D., King G.F.;
RT "A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and
RT the putative drug target acid-sensing ion channel 1a.";
RL Mol. Pharmacol. 80:796-808(2011).
RN [15]
RP STRUCTURE BY NMR IN COMPLEX WITH CHICKEN ASIC1, AND DISULFIDE BOND.
RX PubMed=22842900; DOI=10.1038/nature11375;
RA Baconguis I., Gouaux E.;
RT "Structural plasticity and dynamic selectivity of acid-sensing ion channel-
RT spider toxin complexes.";
RL Nature 489:400-405(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.99 ANGSTROMS) OF 2-38 IN COMPLEX WITH CHICKEN
RP ASIC1, AND DISULFIDE BOND.
RX PubMed=22760635; DOI=10.1038/ncomms1917;
RA Dawson R.J., Benz J., Stohler P., Tetaz T., Joseph C., Huber S., Schmid G.,
RA Hugin D., Pflimlin P., Trube G., Rudolph M.G., Hennig M., Ruf A.;
RT "Structure of the acid-sensing ion channel 1 in complex with the gating
RT modifier Psalmotoxin 1.";
RL Nat. Commun. 3:936-943(2012).
CC -!- FUNCTION: This toxin is a gating modifier that acts principally as an
CC inhibitor on ASIC1a (ASIC isoform 2) and a potentiator on ASIC1b (ASIC
CC isoform 3) (PubMed:10829030, PubMed:15955877, PubMed:21036899). This
CC toxin potently and selectively inhibits rat, mouse and human ASIC1a
CC (IC(50)=0.35-3.7 nM) (PubMed:10829030, PubMed:15955877,
CC PubMed:21715637, PubMed:26248594, PubMed:21825095). The blockade is
CC rapidly reversible (PubMed:10829030, PubMed:28320941). The toxin acts
CC by shifting its steady-state desensitization to more alkaline pH (0.27
CC pH unit) (PubMed:15955877, PubMed:16505147). At higher concentrations,
CC it potentiates rat and human ASIC1b and activates chicken ASIC1 by
CC stabilizing the open state of these subtypes (PubMed:16505147,
CC PubMed:21036899, PubMed:19185346, PubMed:24262969, PubMed:22842900).
CC The toxin binds most tightly to the open and the desensitized states of
CC ASIC1a (promoting desensitization), whereas it binds most tightly to
CC the open state of ASIC1b (promoting opening) (PubMed:16505147). The
CC toxin also inhibits mouse ASIC1a-ASIC2b (IC(50)=2.64 nM) and rat
CC ASIC1a-ASIC2a (PubMed:21715637, PubMed:27277303). It binds to the
CC extracellular domain at subunit interfaces in the acidic pocket with
CC the majority of contacts on the thumb domain of the channel
CC (PubMed:21825095, PubMed:22842900, PubMed:22760635). It is also
CC noteworthy that calcium competes with the toxin, probably by inhibiting
CC binding of the toxin to the channel (PubMed:15955877).
CC {ECO:0000269|PubMed:10829030, ECO:0000269|PubMed:15955877,
CC ECO:0000269|PubMed:16505147, ECO:0000269|PubMed:19185346,
CC ECO:0000269|PubMed:21036899, ECO:0000269|PubMed:21715637,
CC ECO:0000269|PubMed:21825095, ECO:0000269|PubMed:22760635,
CC ECO:0000269|PubMed:22842900, ECO:0000269|PubMed:24262969,
CC ECO:0000269|PubMed:26248594, ECO:0000269|PubMed:27277303,
CC ECO:0000269|PubMed:28320941}.
CC -!- INTERACTION:
CC P60514; Q1XA76: ASIC1; Xeno; NbExp=2; IntAct=EBI-16002043, EBI-15659618;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10829030}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:10829030}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:12824480, ECO:0000269|PubMed:21825095,
CC ECO:0000269|PubMed:22760635, ECO:0000269|PubMed:22842900}.
CC -!- MASS SPECTROMETRY: Mass=4689.25; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:10829030};
CC -!- MASS SPECTROMETRY: Mass=4690; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:12824480};
CC -!- PHARMACEUTICAL: This toxin has been shown to be neuroprotective in both
CC rodent and porcine models of cerebral ischemia when administered 30
CC minutes prior to induction of stroke (PubMed:28457973). In addition, a
CC single dose of this toxin (1 ng/kg, i.c.v. 2 hours post stroke) does
CC indeed provide substantial neuronal and functional protection in
CC ischemic stroke in conscious hypertensive rats (PubMed:26320544).
CC {ECO:0000269|PubMed:26320544, ECO:0000269|PubMed:28457973}.
CC -!- MISCELLANEOUS: This peptide is present at only 0.4% abundance in
CC P.cambridgei venom. {ECO:0000269|PubMed:26320544}.
CC -!- MISCELLANEOUS: Does not act on rat and mouse ASIC1a-ASIC2a
CC (PubMed:10829030, PubMed:21715637). Does not act on rat ASIC1a-ASIC3
CC (PubMed:10829030). {ECO:0000269|PubMed:10829030,
CC ECO:0000269|PubMed:21715637}.
CC -!- SIMILARITY: Belongs to the psalmotoxin-1 family. {ECO:0000305}.
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DR PDB; 1LMM; NMR; -; A=1-40.
DR PDB; 2KNI; NMR; -; A=1-40.
DR PDB; 3S3X; X-ray; 2.99 A; D/E/F=2-38.
DR PDB; 4FZ0; X-ray; 2.80 A; M/N/O=1-40.
DR PDB; 4FZ1; X-ray; 3.36 A; D=1-40.
DR PDBsum; 1LMM; -.
DR PDBsum; 2KNI; -.
DR PDBsum; 3S3X; -.
DR PDBsum; 4FZ0; -.
DR PDBsum; 4FZ1; -.
DR AlphaFoldDB; P60514; -.
DR BMRB; P60514; -.
DR SMR; P60514; -.
DR DIP; DIP-59909N; -.
DR IntAct; P60514; 1.
DR TCDB; 8.B.10.1.1; the psalmotoxin-1 (pctx1) family.
DR ArachnoServer; AS000400; pi-theraphotoxin-Pc1a.
DR EvolutionaryTrace; P60514; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0099106; F:ion 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; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Pharmaceutical;
KW Proton-gated sodium channel impairing toxin; Secreted; Toxin.
FT PEPTIDE 1..40
FT /note="Psalmotoxin-1"
FT /evidence="ECO:0000269|PubMed:10829030"
FT /id="PRO_0000044965"
FT SITE 7
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000269|PubMed:26248594"
FT SITE 24
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:21825095,
FT ECO:0000269|PubMed:22760635, ECO:0000269|PubMed:22842900"
FT SITE 26
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:21825095,
FT ECO:0000269|PubMed:22760635, ECO:0000269|PubMed:22842900"
FT SITE 27
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:21825095,
FT ECO:0000269|PubMed:22760635, ECO:0000269|PubMed:22842900"
FT SITE 28
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000269|PubMed:26248594"
FT SITE 30
FT /note="Key residue for interaction with ASIC1a"
FT /evidence="ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000269|PubMed:26248594"
FT DISULFID 3..18
FT /evidence="ECO:0000269|PubMed:12824480,
FT ECO:0000269|PubMed:21825095, ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000312|PDB:1LMM,
FT ECO:0000312|PDB:2KNI, ECO:0000312|PDB:3S3X,
FT ECO:0000312|PDB:4FZ0, ECO:0000312|PDB:4FZ1"
FT DISULFID 10..23
FT /evidence="ECO:0000269|PubMed:12824480,
FT ECO:0000269|PubMed:21825095, ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000312|PDB:1LMM,
FT ECO:0000312|PDB:2KNI, ECO:0000312|PDB:3S3X,
FT ECO:0000312|PDB:4FZ0, ECO:0000312|PDB:4FZ1"
FT DISULFID 17..33
FT /evidence="ECO:0000269|PubMed:12824480,
FT ECO:0000269|PubMed:21825095, ECO:0000269|PubMed:22760635,
FT ECO:0000269|PubMed:22842900, ECO:0000312|PDB:1LMM,
FT ECO:0000312|PDB:2KNI, ECO:0000312|PDB:3S3X,
FT ECO:0000312|PDB:4FZ0, ECO:0000312|PDB:4FZ1"
FT MUTAGEN 1..2
FT /note="Missing: 1.6-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 6
FT /note="K->A: 97.7-fold decrease in ability to inhibit
FT rASIC1a channel, probably due to structural perturbations."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 7
FT /note="W->A: Complete loss in ability to inhibit rASIC1a
FT channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 8
FT /note="K->A: 1.7-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 14
FT /note="H->A: No change in ability to inhibit rASIC1a
FT channel."
FT /evidence="ECO:0000269|PubMed:21825095"
FT MUTAGEN 24
FT /note="W->A: 170-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:21825095"
FT MUTAGEN 25
FT /note="K->A: No change in ability to inhibit rASIC1a
FT channel."
FT /evidence="ECO:0000269|PubMed:21825095"
FT MUTAGEN 26
FT /note="R->A: Loss of ability to inhibit rASIC1a at low
FT concentration and gain of function as a positive modulator
FT at high concentrations (>100 nM), probably by stabilizing
FT the open state of the channel."
FT /evidence="ECO:0000269|PubMed:21825095"
FT MUTAGEN 27
FT /note="R->A: 165-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:21825095"
FT MUTAGEN 28
FT /note="R->A: 14.5-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 29
FT /note="S->A: Does not significantly modify the ability to
FT inhibit rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 30
FT /note="F->A: Loss of ability to inhibit rASIC1a at low
FT concentration and gain of function as a positive modulator
FT at high concentrations, probably by stabilizing the open
FT state of the channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 31
FT /note="E->A: 2.2-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 32
FT /note="V->A: 17.9-fold decrease in ability to inhibit
FT rASIC1a channel, probably due to structural perturbations."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 34
FT /note="V->A: 1.4-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 35
FT /note="P->A: 2.7-fold increase in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 36
FT /note="K->A: 1.8-fold increase in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 37
FT /note="T->A: Does not significantly modify the ability to
FT inhibit rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 38..40
FT /note="Missing: 4.1-fold decrease in ability to inhibit
FT rASIC1a channel, probably due to the deletion of P-38."
FT /evidence="ECO:0000269|PubMed:26248594"
FT MUTAGEN 38
FT /note="P->A: 3.9-fold decrease in ability to inhibit
FT rASIC1a channel."
FT /evidence="ECO:0000269|PubMed:26248594"
FT STRAND 2..4
FT /evidence="ECO:0007829|PDB:2KNI"
FT STRAND 6..8
FT /evidence="ECO:0007829|PDB:2KNI"
FT TURN 11..14
FT /evidence="ECO:0007829|PDB:1LMM"
FT STRAND 18..20
FT /evidence="ECO:0007829|PDB:1LMM"
FT STRAND 21..24
FT /evidence="ECO:0007829|PDB:4FZ0"
FT STRAND 27..29
FT /evidence="ECO:0007829|PDB:4FZ0"
FT STRAND 32..35
FT /evidence="ECO:0007829|PDB:4FZ0"
SQ SEQUENCE 40 AA; 4695 MW; A52DC98962D9598C CRC64;
EDCIPKWKGC VNRHGDCCEG LECWKRRRSF EVCVPKTPKT
