TX1A_HETMC
ID TX1A_HETMC Reviewed; 35 AA.
AC P60992;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 1.
DT 25-MAY-2022, entry version 67.
DE RecName: Full=Delta-theraphotoxin-Hm1a {ECO:0000303|PubMed:27281198};
DE Short=Delta-TRTX-Hm1a {ECO:0000305|PubMed:12065754};
DE AltName: Full=Heteroscodratoxin-1 {ECO:0000303|PubMed:12065754};
DE Short=HmTx1 {ECO:0000303|PubMed:12065754};
DE AltName: Full=Kappa-theraphotoxin-Hm1a {ECO:0000303|PubMed:27281198};
DE Short=Kappa-TRTX-Hm1a {ECO:0000305|PubMed:27281198};
OS Heteroscodra maculata (Togo starburst tarantula) (Togo starburst baboon
OS spider).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Heteroscodra.
OX NCBI_TaxID=268413;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, MASS SPECTROMETRY,
RP BIOASSAY, AND 3D-STRUCTURE MODELING.
RC TISSUE=Venom;
RX PubMed=12065754; DOI=10.1124/mol.62.1.48;
RA Escoubas P., Diochot S., Celerier M.-L., Nakajima T., Lazdunski M.;
RT "Novel tarantula toxins for subtypes of voltage-dependent potassium
RT channels in the Kv2 and Kv4 subfamilies.";
RL Mol. Pharmacol. 62:48-57(2002).
RN [2]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, MASS SPECTROMETRY, AND
RP BIOASSAY.
RC TISSUE=Venom;
RX PubMed=27281198; DOI=10.1038/nature17976;
RA Osteen J.D., Herzig V., Gilchrist J., Emrick J.J., Zhang C., Wang X.,
RA Castro J., Garcia-Caraballo S., Grundy L., Rychkov G.Y., Weyer A.D.,
RA Dekan Z., Undheim E.A., Alewood P., Stucky C.L., Brierley S.M.,
RA Basbaum A.I., Bosmans F., King G.F., Julius D.;
RT "Selective spider toxins reveal a role for the Nav1.1 channel in mechanical
RT pain.";
RL Nature 534:494-499(2016).
RN [3]
RP MASS SPECTROMETRY, AND STABILITY IN CEREBROSPINAL FLUID AND SERUM.
RC TISSUE=Venom;
RX PubMed=32335140; DOI=10.1016/j.bcp.2020.113991;
RA Chow C.Y., Chin Y.K.Y., Ma L., Undheim E.A.B., Herzig V., King G.F.;
RT "A selective Nav1.1 activator with potential for treatment of Dravet
RT syndrome epilepsy.";
RL Biochem. Pharmacol. 181:113991-113991(2020).
RN [4]
RP STRUCTURE BY NMR, FUNCTION, DISULFIDE BOND, PHARMACEUTICAL, BIOASSAY ON
RP DRAVET SYNDROME MICE MODEL, STABILITY IN CEREBROSPINAL FLUID, AND
RP RECOMBINANT EXPRESSION.
RX PubMed=30076230; DOI=10.1073/pnas.1804764115;
RA Richards K.L., Milligan C.J., Richardson R.J., Jancovski N., Grunnet M.,
RA Jacobson L.H., Undheim E.A.B., Mobli M., Chow C.Y., Herzig V., Csoti A.,
RA Panyi G., Reid C.A., King G.F., Petrou S.;
RT "Selective Nav1.1 activation rescues Dravet syndrome mice from seizures and
RT premature death.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E8077-E8085(2018).
CC -!- FUNCTION: Gating-modifier toxin that potently inhibits inactivation of
CC the mammalian Nav1.1/SCN1A sodium channel (EC(50)=38 nM)
CC (PubMed:27281198, PubMed:30076230). Also moderately inhibits
CC inactivation of Nav1.2/SCN2A (EC(50)=236 nM) and Nav1.3/SCN3A
CC (EC(50)=220 nM) when the channels are expressed in oocytes without the
CC beta-1 auxiliary subunit (PubMed:27281198). Does not inhibit
CC inactivation of Nav1.2/SCN2A when the channel is coexpressed with the
CC beta-1 auxiliary subunit (PubMed:30076230). When tested on Nav1.1/SCN1A
CC channel, it enhances peak current amplitude and potently delays channel
CC inactivation in a dose-dependent manner, leading to a large sustained
CC current (PubMed:30076230). It has no effect on the voltage-dependence
CC of steady-state activation, and induces a depolarizing shift in the
CC voltage dependence of inactivation (PubMed:30076230). In addition, it
CC does not modify the recovery from fast inactivation in Nav1.1/SCN1A
CC (PubMed:30076230). The binding affinity and subtype selectivity of the
CC toxin towards Nav1.1/SCN1A channel is determined by residues within
CC both the S1-S2 and S3-S4 loops of the domain IV voltage sensor of the
CC channel (PubMed:27281198). This toxin also weakly inhibits several
CC subtypes of voltage-gated potassium channels (PubMed:27281198). It
CC moderately blocks Kv2.1/KCNB1 (23% inhibition at 100 nM), Kv2.2/KCNB2
CC (19.7% at 100 nM and 51% at 300 nM), Kv4.1/KCND1 (IC(50)=280 nM),
CC Kv4.2/KCND2 (39% at 300 nM) and Kv4.3/KCND3 (43% at 300 nM)
CC (PubMed:12065754). In vivo, intracerebroventricular injection into mice
CC elicits convulsions, spasms, tremors and rapid death (PubMed:12065754).
CC When injected into mouse hindpaw, the toxin elicits an immediate and
CC robust response to pain (PubMed:27281198). However, intraplantar
CC injection of toxin does not cause neurogenic inflammation or alter
CC sensitivity to heat, indicative of a modality-specific effect on
CC mechanosensitive neurons (PubMed:27281198). In Dravet syndrome mice
CC model, intracerebroventricular infusion of this peptide rescues mice
CC from seizures and premature death (PubMed:30076230).
CC {ECO:0000269|PubMed:12065754, ECO:0000269|PubMed:27281198,
CC ECO:0000269|PubMed:30076230}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12065754,
CC ECO:0000269|PubMed:27281198}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:12065754, ECO:0000305|PubMed:27281198}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:30076230}.
CC -!- MASS SPECTROMETRY: Mass=3994.59; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:12065754};
CC -!- MASS SPECTROMETRY: Mass=3995.55; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:27281198};
CC -!- MASS SPECTROMETRY: Mass=3995.51; Method=MALDI; Note=Monoisotopic mass.;
CC Evidence={ECO:0000269|PubMed:32335140};
CC -!- PHARMACEUTICAL: May be used to develop new agents to treat
CC Nav1.1/SCN1A-associated epilepsies, such as the Dravet syndrome. In
CC Dravet syndrome mice model, by a selective activation of Nav1.1/SCN1A
CC channels, this peptide restores the function of inhibitory interneurons
CC without affecting the firing of excitatory neurons.
CC {ECO:0000305|PubMed:30076230}.
CC -!- MISCELLANEOUS: Shows poor stability in cerebrospinal fluid and moderate
CC stability in human serum (PubMed:32335140, PubMed:30076230). Half-life
CC of the toxin is about 1.7 hour in cerebrospinal fluid
CC (PubMed:30076230). Half-life of the native toxin is about 10 hours in
CC human serum (PubMed:32335140). {ECO:0000269|PubMed:30076230,
CC ECO:0000269|PubMed:32335140}.
CC -!- MISCELLANEOUS: Does not inhibit Nav1.4/SCN4A, Nav1.5/SCN5A,
CC Nav1.6/SCN8A, Nav1.7/SCN9A, and Nav1.8/SCN10A at concentrations up to
CC 50 nM or 1 uM (PubMed:27281198, PubMed:30076230). Does not inhibit
CC Nav1.2/SCN2A at concentrations up to 50 nM (PubMed:30076230). Has no or
CC very weak effect on Kv1.1/KCNA1, Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.4/KCNA4,
CC Kv1.5/KCNA5, Kv1.6/KCNA6 and Kv3.4/KCNC4 (PubMed:12065754). Does not
CC show significant effects on Kv1.7/KCNQ1, Kv10.1/KCNH1/EAG1,
CC Kv11.1/KCNH2/ERG1, KCa1.1/KCNMA1, KCa2.1/KCNN1 and KCa2.3/KCNN3
CC (PubMed:12065754). {ECO:0000269|PubMed:12065754,
CC ECO:0000269|PubMed:27281198, ECO:0000269|PubMed:30076230}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 09 (HaTx)
CC subfamily. {ECO:0000305}.
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DR PDB; 2N6O; NMR; -; A=1-35.
DR PDBsum; 2N6O; -.
DR AlphaFoldDB; P60992; -.
DR BMRB; P60992; -.
DR SMR; P60992; -.
DR TCDB; 8.B.5.3.3; the na(+)/k(+)/ca(2+) channel targeting tarantula huwentoxin (tht) family.
DR ArachnoServer; AS000224; delta-theraphotoxin-Hm1a.
DR GO; GO:0005576; C:extracellular region; 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; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0044488; P:modulation of voltage-gated sodium channel activity in another organism; IDA:UniProtKB.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Pharmaceutical;
KW Potassium channel impairing toxin; Secreted; Toxin;
KW Voltage-gated potassium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..35
FT /note="Delta-theraphotoxin-Hm1a"
FT /evidence="ECO:0000269|PubMed:12065754,
FT ECO:0000269|PubMed:27281198"
FT /id="PRO_0000045017"
FT DISULFID 2..16
FT /evidence="ECO:0000269|PubMed:30076230,
FT ECO:0007744|PDB:2N6O"
FT DISULFID 9..21
FT /evidence="ECO:0000269|PubMed:30076230,
FT ECO:0007744|PDB:2N6O"
FT DISULFID 15..28
FT /evidence="ECO:0000269|PubMed:30076230,
FT ECO:0007744|PDB:2N6O"
FT TURN 5..7
FT /evidence="ECO:0007829|PDB:2N6O"
FT HELIX 12..14
FT /evidence="ECO:0007829|PDB:2N6O"
FT TURN 23..26
FT /evidence="ECO:0007829|PDB:2N6O"
SQ SEQUENCE 35 AA; 4003 MW; B9A84D9FF50AE603 CRC64;
ECRYLFGGCS STSDCCKHLS CRSDWKYCAW DGTFS
