UniProt functional annotation for P83303



	UniProt functional annotation for P83303

UniProt code: P83303.

Organism: Cyriopagopus schmidti (Chinese bird spider) (Haplopelma schmidti).

Taxonomy: Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae; Mygalomorphae; Theraphosidae; Haplopelma.

Function: This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel Nav1.2/SCN2A (IC(50)=10- 150 nM), rNav1.3/SCN3A (IC(50)=338 nM), Nav1.6/SCN8A (IC(50)=117 nM), and hNav1.7/SCN9A (IC(50)=9.6-33 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, PubMed:29703751,PubMed:31234412, PubMed:23760503). It inhibits activation of sodium channel by trapping the voltage sensor of domain II (DIIS4) in the closed configuration (PubMed:18628201, PubMed:23760503). The toxin neither shifts the Nav1.7/SCN9A activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7/SCN9A channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, PubMed:29703751, PubMed:28115115). This toxin also exists with a pyroglutamate at position 53 (PubMed:23826086). The sole difference observed between modified (mHwTx-IV) and unmodified toxins is that moderate or high depolarization voltages (200 mV) permit the unmodified toxin to dissociate, whereas mHwTx-IV toxin does not dissociate, even at high depolarization voltages (PubMed:23826086). These data indicate that mHwTx-IV strongly binds to voltage sensor of sodium channel even at extreme depolarization voltages (PubMed:23826086). {ECO:0000269|PubMed:12228241, ECO:0000269|PubMed:18054060, ECO:0000269|PubMed:18628201, ECO:0000269|PubMed:20855463, ECO:0000269|PubMed:21659528, ECO:0000269|PubMed:23523779, ECO:0000269|PubMed:23760503, ECO:0000269|PubMed:25658507, ECO:0000269|PubMed:28115115, ECO:0000269|PubMed:29483648}.

Subcellular location: Secreted {ECO:0000269|PubMed:12228241}.

Tissue specificity: Expressed by the venom gland. {ECO:0000305|PubMed:12228241}.

Domain: The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. {ECO:0000269|PubMed:12228241, ECO:0000269|PubMed:23760503, ECO:0000269|PubMed:28115115}.

Ptm: Two forms of huwentoxin-IV exist in the venom of H.schmidti, a non-N-terminally modified (HwTx-IV) and a naturally modified peptide with pyroglutamic acid residue at position 53 (mHwTx-IV). mHwTx-IV shows no observable difference with the unmodified toxin when applied to the TTX-S sodium channel of DRG neuron (IC(50)~50 nM) or when tested on hNav1.7/SCN9A (IC(50)=30.8 nM) (PubMed:23826086, PubMed:28115115). In addition, similarly to the unmodified toxin, mHwTx-IV has only a weak affinity for lipid membranes (PubMed:28115115). However, in contrast with HwTx-IV, which dissociates at moderate and high depolarization voltages (50-200 mV), mHwTx-IV inhibition of TTX- sensitive sodium channels is not reversed by strong depolarization voltages (PubMed:23826086). {ECO:0000269|PubMed:23826086, ECO:0000269|PubMed:28115115}.

Mass spectrometry: Mass=4089.64; Method=MALDI; Note=mhuwentoxin-IV (with pyrrolidone carboxylic acid (Glu) at position 53).; Evidence={ECO:0000269|PubMed:23826086};

Mass spectrometry: Mass=4107.94; Method=MALDI; Note=huwentoxin-IV (with unmodified Glu at position 53).; Evidence={ECO:0000269|PubMed:23826086};

Mass spectrometry: Mass=4107.5; Method=MALDI; Note=huwentoxin-IV (with unmodified Glu at position 53).; Evidence={ECO:0000269|PubMed:18054060};

Miscellaneous: Shows a weak or no inhibition on rNav1.4/SCN4A (IC(50)=3.9->10 uM) and hNav1.5/SCN5A sodium channels (IC(50)=>10-25 uM) (PubMed:18628201, PubMed:25658507). This toxin has also been shown to weakly inhibit Kv11.1/KCNH2/ERG1, Kv1.2/KCNA2 and Kv1.3/KCNA3 (PubMed:29483648). {ECO:0000269|PubMed:18628201, ECO:0000269|PubMed:25658507, ECO:0000269|PubMed:29483648}.

Similarity: Belongs to the neurotoxin 10 (Hwtx-1) family. 22 (Htx-4) subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Cyriopagopus schmidti (Chinese bird spider) (Haplopelma schmidti).
Taxonomy:		Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae; Mygalomorphae; Theraphosidae; Haplopelma.



Function:		This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel Nav1.2/SCN2A (IC(50)=10- 150 nM), rNav1.3/SCN3A (IC(50)=338 nM), Nav1.6/SCN8A (IC(50)=117 nM), and hNav1.7/SCN9A (IC(50)=9.6-33 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, PubMed:29703751,PubMed:31234412, PubMed:23760503). It inhibits activation of sodium channel by trapping the voltage sensor of domain II (DIIS4) in the closed configuration (PubMed:18628201, PubMed:23760503). The toxin neither shifts the Nav1.7/SCN9A activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7/SCN9A channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, PubMed:29703751, PubMed:28115115). This toxin also exists with a pyroglutamate at position 53 (PubMed:23826086). The sole difference observed between modified (mHwTx-IV) and unmodified toxins is that moderate or high depolarization voltages (200 mV) permit the unmodified toxin to dissociate, whereas mHwTx-IV toxin does not dissociate, even at high depolarization voltages (PubMed:23826086). These data indicate that mHwTx-IV strongly binds to voltage sensor of sodium channel even at extreme depolarization voltages (PubMed:23826086). {ECO:0000269\|PubMed:12228241, ECO:0000269\|PubMed:18054060, ECO:0000269\|PubMed:18628201, ECO:0000269\|PubMed:20855463, ECO:0000269\|PubMed:21659528, ECO:0000269\|PubMed:23523779, ECO:0000269\|PubMed:23760503, ECO:0000269\|PubMed:25658507, ECO:0000269\|PubMed:28115115, ECO:0000269\|PubMed:29483648}.


Subcellular location:		Secreted {ECO:0000269\|PubMed:12228241}.
Tissue specificity:		Expressed by the venom gland. {ECO:0000305\|PubMed:12228241}.
Domain:		The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin. {ECO:0000269\|PubMed:12228241, ECO:0000269\|PubMed:23760503, ECO:0000269\|PubMed:28115115}.
Ptm:		Two forms of huwentoxin-IV exist in the venom of H.schmidti, a non-N-terminally modified (HwTx-IV) and a naturally modified peptide with pyroglutamic acid residue at position 53 (mHwTx-IV). mHwTx-IV shows no observable difference with the unmodified toxin when applied to the TTX-S sodium channel of DRG neuron (IC(50)~50 nM) or when tested on hNav1.7/SCN9A (IC(50)=30.8 nM) (PubMed:23826086, PubMed:28115115). In addition, similarly to the unmodified toxin, mHwTx-IV has only a weak affinity for lipid membranes (PubMed:28115115). However, in contrast with HwTx-IV, which dissociates at moderate and high depolarization voltages (50-200 mV), mHwTx-IV inhibition of TTX- sensitive sodium channels is not reversed by strong depolarization voltages (PubMed:23826086). {ECO:0000269\|PubMed:23826086, ECO:0000269\|PubMed:28115115}.
Mass spectrometry:		Mass=4089.64; Method=MALDI; Note=mhuwentoxin-IV (with pyrrolidone carboxylic acid (Glu) at position 53).; Evidence={ECO:0000269\|PubMed:23826086};
Mass spectrometry:		Mass=4107.94; Method=MALDI; Note=huwentoxin-IV (with unmodified Glu at position 53).; Evidence={ECO:0000269\|PubMed:23826086};
Mass spectrometry:		Mass=4107.5; Method=MALDI; Note=huwentoxin-IV (with unmodified Glu at position 53).; Evidence={ECO:0000269\|PubMed:18054060};
Miscellaneous:		Shows a weak or no inhibition on rNav1.4/SCN4A (IC(50)=3.9->10 uM) and hNav1.5/SCN5A sodium channels (IC(50)=>10-25 uM) (PubMed:18628201, PubMed:25658507). This toxin has also been shown to weakly inhibit Kv11.1/KCNH2/ERG1, Kv1.2/KCNA2 and Kv1.3/KCNA3 (PubMed:29483648). {ECO:0000269\|PubMed:18628201, ECO:0000269\|PubMed:25658507, ECO:0000269\|PubMed:29483648}.
Similarity:		Belongs to the neurotoxin 10 (Hwtx-1) family. 22 (Htx-4) subfamily. {ECO:0000305}.