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Protein

Huwentoxin-IV

Gene
N/A
Organism
Haplopelma schmidti (Chinese bird spider) (Ornithoctonus huwenum)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

This lethal neurotoxin (without cyclization at position 53) inhibits neuronal voltage-gated sodium channel hNav1.7/SCN9A (IC50 is 22-33 nM), rNav1.2/SCN2A (IC50 is 150 nM), and rNav1.3/SCN3A (IC50 is 338 nM) (PubMed:18628201, PubMed:20855463, PubMed:25658507, 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 activation curve nor modifies the slope factor (PubMed:20855463). It does not slow fast-inactivation of hNav1.7 channels (PubMed:20855463). In addition, it has only a weak affinity for lipid membranes (PubMed:18054060, 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).9 Publications

Miscellaneous

Shows a weak or no inhibition on rNav1.4/SCN4A (IC50=3.9 µM) and hNav1.5/SCN5A sodium channels (IC50=25->10 µM).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei58Binds to the extracellular loop of voltage sensor domain II of sodium channels (Nav1.2/SCN2A and Nav1.7/SCN9A)1 Publication1
Sitei78Binds to the extracellular loop of voltage sensor domain II of sodium channels (Nav1.2/SCN2A and Nav1.7/SCN9A)1 Publication1
Sitei79Binds to the extracellular loop of voltage sensor domain II of sodium channels (Nav1.2/SCN2A and Nav1.7/SCN9A)1 Publication1
Sitei82Binds to the extracellular loop of voltage sensor domain II of sodium channels (Nav1.2/SCN2A and Nav1.7/SCN9A)1 Publication1
Sitei84Binds to the extracellular loop of voltage sensor domain II of sodium channels (Nav1.2/SCN2A and Nav1.7/SCN9A)1 Publication1

GO - Molecular functioni

Keywordsi

Molecular functionIon channel impairing toxin, Neurotoxin, Presynaptic neurotoxin, Toxin, Voltage-gated sodium channel impairing toxin

Protein family/group databases

TCDBi8.B.3.1.3. the huwentoxin-1 (huwentoxin-1) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Huwentoxin-IV1 Publication
Short name:
HwTx-IV1 Publication
Alternative name(s):
Huwentoxin-4Curated
Huwentoxin-IVaImported
Short name:
HWTX-IVaImported
Huwentoxin-IVbImported
Short name:
HWTX-IVbImported
Huwentoxin-IVcImported
Short name:
HWTX-IVcImported
Mu-theraphotoxin-Hs2a1 Publication
Short name:
Mu-TRTX-Hs2a1 Publication
OrganismiHaplopelma schmidti (Chinese bird spider) (Ornithoctonus huwenum)
Taxonomic identifieri29017 [NCBI]
Taxonomic lineageiEukaryotaMetazoaEcdysozoaArthropodaChelicerataArachnidaAraneaeMygalomorphaeTheraphosidaeHaplopelma

Organism-specific databases

ArachnoServeriAS000332. mu-theraphotoxin-Hs2a.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi53 – 56ECLE → ACLA: 6-fold increase in ability to inhibit hNav1.7/SCN9A. 28-fold increase in ability to inhibit hNav1.7/SCN9A; when associated with W-85. 1 Publication4
Mutagenesisi53 – 56ECLE → GCLG: 34-fold increase in ability to inhibit hNav1.7/SCN9A. In m3-huwentoxin-IV; 43-fold increase in ability to inhibit hNav1.7/SCN9A. In m3-huwentoxin-IV; potently inhibits Nav1.1/SCN1A, Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.6/SCN8A and Nav1.7/SCN9A. In gHuwentoxin-IV; shows higher affinity for lipid membranes and a 4-fold increase in ability to inhibit hNav1.7/SCN9A compared to both huwentoxin-IV and mhuwentoxin-IV. 3 Publications4
Mutagenesisi53E → A: 2.8-fold increase in ability to inhibit hNav1.7/SCN9A, and no change in activity on hNav1.5/SCN5A. 1 Publication1
Mutagenesisi56E → A: No change in activity on both Nav1.2/SCN2A and hNav1.5/SCN5A, and contreversial activity on Nav1.7/SCN9A. Small increase in ability to inhibit Nav1.7/SCN9A (according to PMID:23760503), and 1.5-fold decrease in ability to inhibit hNav1.7/SCN9A (according to PMID:23523779). 2 Publications1
Mutagenesisi58F → A: Important decrease in ability to inhibit Nav1.2/SCN2A, and small decrease in ability to inhibit Nav1.7/SCN9A. 1 Publication1
Mutagenesisi58F → W in gHuwentoxin-IV; shows higher affinity for lipid membranes and a 4-fold increase in ability to inhibit hNav1.7/SCN9A compared to both huwentoxin-IV and mhuwentoxin-IV. 1 Publication1
Mutagenesisi63P → A: Important decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi66D → A: Important decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi74L → A: Important decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi77S → A: Important decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi78R → A: Important decrease in ability to inhibit Nav1.2/SCN2A, and no change in activity on Nav1.7/SCN9A. 1 Publication1
Mutagenesisi79K → A: Important decrease in ability to inhibit Nav1.2/SCN2A, and no change in activity on Nav1.7/SCN9A. 1 Publication1
Mutagenesisi81R → A: Small decrease in ability to inhibit Nav1.2/SCN2A, and no change in activity on Nav1.7/SCN9A. 1 Publication1
Mutagenesisi82W → A: Almost complete loss in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi84K → A: Almost complete loss in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi85Y → A: Important decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1
Mutagenesisi85Y → W: 12-fold increase in ability to inhibit hNav1.7/SCN9A, and no change in activity on hNav1.5/SCN5A. In m3-huwentoxin-IV; 43-fold increase in ability to inhibit hNav1.7/SCN9A. In m3-huwentoxin-IV; potently inhibits Nav1.1/SCN1A, Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.6/SCN8A and Nav1.7/SCN9A. In gHuwentoxin-IV; shows higher affinity for lipid membranes and a 4-fold increase in ability to inhibit hNav1.7/SCN9A compared to both huwentoxin-IV and mhuwentoxin-IV. 3 Publications1
Mutagenesisi87I → A: Small decrease in ability to inhibit both Nav1.2/SCN2A and Nav1.7/SCN9A. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
PropeptideiPRO_000003556025 – 521 PublicationAdd BLAST28
ChainiPRO_000003556153 – 87Huwentoxin-IV1 PublicationAdd BLAST35

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei53Pyrrolidone carboxylic acid (Glu); alternate1 Publication1
Disulfide bondi54 ↔ 691 PublicationImported
Disulfide bondi61 ↔ 761 PublicationImported
Disulfide bondi68 ↔ 831 PublicationImported
Modified residuei87Isoleucine amide1 Publication1

Post-translational modificationi

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 (IC50~50 nM) or when tested on hNav1.7/SCN9A (IC50=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).2 Publications

Keywords - PTMi

Amidation, Disulfide bond, Pyrrolidone carboxylic acid

Expressioni

Tissue specificityi

Expressed by the venom gland.1 Publication

Structurei

Secondary structure

189
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi57 – 60Combined sources4
Beta strandi63 – 65Combined sources3
Turni70 – 73Combined sources4
Beta strandi74 – 77Combined sources4
Turni78 – 81Combined sources4
Beta strandi82 – 85Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1MB6NMR-A53-87[»]
2M4XNMR-A53-87[»]
2M4ZNMR-A53-87[»]
2M50NMR-A53-87[»]
5T3MNMR-A53-87[»]
5TLRNMR-A53-87[»]
ProteinModelPortaliP83303.
SMRiP83303.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP83303.

Family & Domainsi

Domaini

The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin.3 Publications

Sequence similaritiesi

Belongs to the huwentoxin-1 family. Htx-4 subfamily.Curated

Keywords - Domaini

Knottin, Signal

Family and domain databases

InterProiView protein in InterPro
IPR011696. Huwentoxin-1.
IPR013140. Huwentoxin_CS1.
PfamiView protein in Pfam
PF07740. Toxin_12. 1 hit.
PROSITEiView protein in PROSITE
PS60021. HWTX_1. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P83303-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVNMKASMFL ALAGLVLLFV VCYASESEEK EFSNELLSSV LAVDDNSKGE
60 70 80
ERECLEIFKA CNPSNDQCCK SSKLVCSRKT RWCKYQIGK
Length:89
Mass (Da):9,997
Last modified:November 23, 2004 - v2
Checksum:i39CCC6FC1ADCBC75
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti17L → Q in ABY77746 (PubMed:18482741).1 Publication1
Sequence conflicti85Y → C in ABY77745 (PubMed:18482741).1 Publication1

Mass spectrometryi

Molecular mass is 4089.64 Da from positions 53 - 87. Determined by MALDI. mhuwentoxin-IV (with pyrrolidone carboxylic acid (Glu) at position 53).1 Publication
Molecular mass is 4107.94 Da from positions 53 - 87. Determined by MALDI. huwentoxin-IV (with unmodified Glu at position 53).1 Publication
Molecular mass is 4107.5 Da from positions 53 - 87. Determined by MALDI. huwentoxin-IV (with unmodified Glu at position 53).1 Publication

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY263707 mRNA. Translation: AAP33074.1.
EU195291 mRNA. Translation: ABY77744.1.
EU195292 mRNA. Translation: ABY77745.1.
EU195293 mRNA. Translation: ABY77746.1.

Similar proteinsi

Entry informationi

Entry nameiTXH4_HAPSC
AccessioniPrimary (citable) accession number: P83303
Secondary accession number(s): B3FIU7
, B3FIU8, B3FIU9, Q86C52
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 20, 2002
Last sequence update: November 23, 2004
Last modified: November 22, 2017
This is version 84 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programAnimal Toxin Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Direct protein sequencing

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families