TP1A_HADIN
ID TP1A_HADIN Reviewed; 75 AA.
AC A0A1L1QJU3; A0A1X8XKZ9;
DT 07-JUN-2017, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2017, sequence version 2.
DT 25-MAY-2022, entry version 14.
DE RecName: Full=Pi-hexatoxin-Hi1a {ECO:0000303|PubMed:28320941};
DE Short=Pi-HXTX-Hi1a {ECO:0000303|PubMed:28320941};
DE AltName: Full=Double-knot toxin {ECO:0000305};
DE Short=DkTx {ECO:0000305};
OS Hadronyche infensa (Fraser island funnel-web spider) (Atrax infensus).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Hexathelidae; Hadronyche.
OX NCBI_TaxID=153481;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], STRUCTURE BY NMR, DISULFIDE BOND, AND
RP MUTAGENESIS OF 1-ASN--VAL-34; ASN-1; PRO-35 AND 36-ILE--THR-75.
RC TISSUE=Venom gland;
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 [2]
RP FUNCTION.
RX PubMed=31213240; DOI=10.1016/j.vetpar.2019.05.008;
RA Nixon S.A., Saez N.J., Herzig V., King G.F., Kotze A.C.;
RT "The antitrypanosomal diarylamidines, diminazene and pentamidine, show
RT anthelmintic activity against Haemonchus contortus in vitro.";
RL Vet. Parasitol. 270:40-46(2019).
CC -!- FUNCTION: This toxin potently and selectively inhibits ASIC1a
CC (IC(50)=0.4 nM on rASIC1a and IC(50)=0.52 nM on hASIC1a), an isoform of
CC the gene ASIC1 (PubMed:28320941). It incompletely inhibits ASIC1a
CC activation in a pH-independent and slowly reversible manner
CC (Tau(off)=14.2 min for rASIC1a and 31.8 min for hASIC1a)
CC (PubMed:28320941). This toxin acts by binding to and stabilizing the
CC closed state of the channel, thereby impeding the transition into a
CC conducting state (PubMed:28320941). This toxin may bind to the acidic
CC pocket of ASIC1a, since mutation of a key residue of this pocket (Arg-
CC 350) abolishes the ability of the toxin to inhibit ASIC1a
CC (PubMed:28320941). In addition, it shows antiparasitic activities,
CC since it moderately inhibits the larval development of the major
CC pathogenic nematode of ruminants (H.contortus, IC(50)=22.9 uM)
CC (PubMed:31213240). In vivo, this toxin protects the brain from neuronal
CC injury when administered up to 8 hours after stroke onset
CC (PubMed:28320941). {ECO:0000269|PubMed:28320941,
CC ECO:0000269|PubMed:31213240}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P60514}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:28320941}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin. This toxin contains 2
CC 'disulfide through disulfide knots' that are separated by a short
CC linker. {ECO:0000269|PubMed:28320941}.
CC -!- PHARMACEUTICAL: This toxin is a promising lead for the development of
CC therapeutics to protect the brain from ischemic injury.
CC {ECO:0000305|PubMed:28320941}.
CC -!- SIMILARITY: Belongs to the psalmotoxin-1 family. Double-knot toxin
CC subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Biological Magnetic Resonance Data Bank;
CC URL="http://bmrb.wisc.edu/data_library/summary/index.php?bmrbId=25848#";
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DR PDB; 2N8F; NMR; -; A=1-75.
DR PDBsum; 2N8F; -.
DR AlphaFoldDB; A0A1L1QJU3; -.
DR SMR; A0A1L1QJU3; -.
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; Disulfide bond; Ion channel impairing toxin; Pharmaceutical;
KW Proton-gated sodium channel impairing toxin; Secreted; Toxin.
FT CHAIN 1..75
FT /note="Pi-hexatoxin-Hi1a"
FT /evidence="ECO:0000305|PubMed:28320941"
FT /id="PRO_0000440131"
FT DISULFID 3..18
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT DISULFID 10..23
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT DISULFID 17..33
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT DISULFID 40..55
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT DISULFID 47..60
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT DISULFID 54..71
FT /evidence="ECO:0000269|PubMed:28320941,
FT ECO:0000312|PDB:2N8F"
FT MUTAGEN 1..34
FT /note="Missing: Complete loss of inhibition of rASIC1a;
FT mutant Hi1a:C."
FT /evidence="ECO:0000269|PubMed:28320941"
FT MUTAGEN 1
FT /note="N->SN: 2600-fold decrease in inhibition of rASIC1a,
FT and inhibition become fully reversible; mutant Hi1a:N."
FT /evidence="ECO:0000269|PubMed:28320941"
FT MUTAGEN 35
FT /note="P->S: Complete loss of inhibition of rASIC1a; mutant
FT Hi1a:C."
FT /evidence="ECO:0000269|PubMed:28320941"
FT MUTAGEN 36..75
FT /note="Missing: 2600-fold decrease in inhibition of
FT rASIC1a, and inhibition become fully reversible; mutant
FT Hi1a:N."
FT /evidence="ECO:0000269|PubMed:28320941"
FT STRAND 10..12
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 21..23
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 27..29
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 33..35
FT /evidence="ECO:0007829|PDB:2N8F"
FT TURN 51..53
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 58..61
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 65..68
FT /evidence="ECO:0007829|PDB:2N8F"
FT STRAND 70..73
FT /evidence="ECO:0007829|PDB:2N8F"
SQ SEQUENCE 75 AA; 8648 MW; 15256C6BD1B68328 CRC64;
NECIRKWLSC VDRKNDCCEG LECYKRRHSF EVCVPIPGFC LVKWKQCDGR ERDCCAGLEC
WKRSGNKSSV CAPIT
