PROSITE documentation PDOC60004

Conotoxin families signatures

Description

Cone snail toxins, conotoxins, are small peptides with disulfide connectivity, that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulfide bonds and biological activities, conotoxins can be classified into several families [1]. Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulfide through disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus [2,E1].

Conotoxins represent a unique arsenal of neuropharmacologically active peptides that have been evolutionarily tailored to afford unprecedented and exquisite selectivity for a wide variety of ion-channel subtypes. The toxins derived from cone snails are currently being investigated for the treatment of chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement disorders, spasticity, cancer, stroke as well as an anesthetic agent. Several potential analgesic and anti-inflammatory peptides from conotoxin families have been identified and patented [3,4]:

  • Conus magus omega-conotoxin MVIIa (Ziconotide) is used for the treatment of chronic pain.
  • Conus catus omega-conotoxin CVID is tested for treating severe morphine- resistant pain stress.
  • Conus geographus omega-conotoxin GVIA may exert antagonistic effects against β-endorphin induced anti-nociception.

The disulfide bonding network as well as specific amino acids in inter-cysteine loops provide specificity of conotoxins [5]. The cysteine arrangement [C-C-CC-C-C] is the same for omega and delta families, which belong to the O-superfamily. The omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels [1]. The M-superfamily Mu conotoxins have two types of cysteine arrangement [CC-C-C-CC] and [CC-C-C-C-C], but knottin scaffold is not observed. Mu conotoxins target the voltage-gated sodium channels [1] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues [6]. α conotoxins belong to the A-superfamily and have two types of cysteine arrangement [CC-C-C] and [CCC-C-C-C] [7]. α conotoxins are competitive nicotinic acetylcholine receptor antagonists. The I-superfamily of conotoxins is characterized by a pattern of eight cysteine residues that form four disulfide bridges. The arrangement of cysteine residues is similar to the Janus-faced atracotoxin peptides characterized from spider venoms (see <PDOC60020>) [8,9].

Three signature patterns were developed for omega, delta and mu conotoxin families. The patterns each include six conserved cysteines thought to be important for the maintenance of the tertiary structure of the conotoxins. We have defined a pattern for the common part of the cysteine arrangement [CC-C-C] in all members of α conotoxin family. The pattern includes four conserved cysteines thought to be important for the maintenance of the tertiary structure of α conotoxins. The pattern for the I-superfamily conotoxin covers the eight conserved cysteines.

Expert(s) to contact by email:

Ramakumar S.

Last update:

October 2006 / Pattern for the I-superfamily revised.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

ALPHA_CONOTOXIN, PS60014; Alpha-conotoxin family signature  (PATTERN)
Consensus pattern: C-C-[SHYN]-x(0,1)-[PRG]-[RPATV]-C-[ARMFTNHG]-x(0,4)-[QWHDGENFYVP]-[RIVYLGSDW]-C
The 4 C's are involved in disulfide bonds
Sequences known to belong to this class detected by the pattern: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS60014
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS60014
• Scan Swiss-Prot/TrEMBL entries against PS60014
• view ligand binding statistics
Matching PDB structures: 1A0M 1AKG 1B45 1CNL ... [ALL]
DELTA_CONOTOXIN, PS60005; Delta-conotoxin family signature  (PATTERN)
Consensus pattern: C-x(2)-[EPSAGT]-x(3)-C-[GSNDL]-x(0,3)-[PILV]-x-[FPNDSG]-[GQ]-x-C-C-x(3,4)-C-[FLVIA]-x(1,2)-[FVIWA]-C
The 6 C's are involved in disulfide bonds
Sequences known to belong to this class detected by the pattern: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS60005
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS60005
• Scan Swiss-Prot/TrEMBL entries against PS60005
• view ligand binding statistics
Matching PDB structures: 1FU3 1YZ2 [ALL]
I_CONOTOXIN, PS60019; I-superfamily conotoxin signature  (PATTERN)
Consensus pattern: C-{C}(6)-C-{C}(5)-C-C-x(1,3)-C-C-x(2,4)-C-x(3,10)-C
The 8 C's are involved in disulfide bonds
Sequences known to belong to this class detected by the pattern: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS60019
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS60019
• Scan Swiss-Prot/TrEMBL entries against PS60019
• view ligand binding statistics
Matching PDB structures: 1ZJS 2JRY 2JTU 2P4L [ALL]
MU_CONOTOXIN, PS60013; Mu-conotoxin family signature  (PATTERN)
Consensus pattern: C-C-[TGN]-[PFG]-[PRG]-x(0,2)-C-[KRS]-[DS]-[RK]-[RQW]-C-[KR]-[PD]-[MLQH]-x(0,1)-[KR]-C-C
The 6 C's are involved in disulfide bonds
Sequences known to belong to this class detected by the pattern: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS60013
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS60013
• Scan Swiss-Prot/TrEMBL entries against PS60013
• view ligand binding statistics
OMEGA_CONOTOXIN, PS60004; Omega-conotoxin family signature  (PATTERN)
Consensus pattern: C-[SREYKLIMQVN]-x(2)-[DGWET]-x-[FYSPKV]-C-[GNDSRHTP]-x(1,5)-[NPGSMTAHF]-[GWPNIYRSKLQ]-x-C-C-[STRHGD]-x(0,2)-[NFLWSRYIT]-C-x(0,3)-[VFGAITSNRKL]-[FLIKRNGH]-[VWIARKF]-C
The 6 C's are involved in disulfide bonds
Sequences known to belong to this class detected by the pattern: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS60004
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS60004
• Scan Swiss-Prot/TrEMBL entries against PS60004
• view ligand binding statistics
Matching PDB structures: 1CNN 1DW4 1DW5 1F3K ... [ALL]

References

1 Authors McIntosh J.M., Jones R.M.
Title Cone venom--from accidental stings to deliberate injection.
Source Toxicon 39:1447-1451(2001).
PubMed ID 11478951
2 Authors Gelly J.-C., Gracy J., Kaas Q., Le-Nguyen D., Heitz A., Chiche L.
Title The KNOTTIN website and database: a new information system dedicated to the knottin scaffold.
Source Nucleic Acids Res. 32:D156-D159(2004).
PubMed ID 14681383
DOI 10.1093/nar/gkh015
3 Authors Jones R.M., Bulaj G.
Title Conotoxins - new vistas for peptide therapeutics.
Source Curr. Pharm. Des. 6:1249-1285(2000).
PubMed ID 10903392
4 Authors Rajendra W., Armugam A., Jeyaseelan K.
Title Toxins in anti-nociception and anti-inflammation.
Source Toxicon 44:1-17(2004).
PubMed ID 15225557
DOI 10.1016/j.toxicon.2004.04.014
5 Authors Balaji R.A., Ohtake A., Sato K., Gopalakrishnakone P., Kini R.M., Seow K.T., Bay B.-H.
Title Lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus.
Source J. Biol. Chem. 275:39516-39522(2000).
PubMed ID 10988292
DOI 10.1074/jbc.M006354200
6 Authors Cruz L.J., Gray W.R., Olivera B.M., Zeikus R.D., Kerr L., Yoshikami D., Moczydlowski E.
Title Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
Source J. Biol. Chem. 260:9280-9288(1985).
PubMed ID 2410412
7 Authors Ramilo C.A., Zafaralla G.C., Nadasdi L., Hammerland L.G., Yoshikami D., Gray W.R., Kristipati R., Ramachandran J., Miljanich G., Olivera B.M.
Title Novel alpha- and omega-conotoxins from Conus striatus venom.
Source Biochemistry 31:9919-9926(1992).
PubMed ID 1390774
8 Authors Jimenez E.C., Shetty R.P., Lirazan M., Rivier J., Walker C., Abogadie F.C., Yoshikami D., Cruz L.J., Olivera B.M.
Title Novel excitatory Conus peptides define a new conotoxin superfamily.
Source J. Neurochem. 85:610-621(2003).
PubMed ID 12694387
9 Authors Kauferstein S., Huys I., Kuch U., Melaun C., Tytgat J., Mebs D.
Title Novel conopeptides of the I-superfamily occur in several clades of cone snails.
Source Toxicon 44:539-548(2004).
PubMed ID 15450929
DOI 10.1016/j.toxicon.2004.07.006
E1
Source http://knottin.cbs.cnrs.fr

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