About conotoxins

Conotoxin names

There are inconsistencies in the nomenclature used for naming conotoxins, but in general they tend to be named as follows. The initial categorization of the conopeptides is based on the pharmacological family they belong too and this is denoted by a Greek letter at the beginning of the peptide name. A letter or two is then used to designate the Conus species from which the peptide was isolated, followed by a Roman numeral specifying the disulfide bond connectivity. Conotoxins are also grouped into superfamilies, defined by their signal sequence in the initial prepropeptide and the disulfide framework.

Logo representation of the first 25 amino acids from conotoxin precursors belonging to superfamily A as of September 2007.

Although peptides within the same superfamily have a particular disulfide bond framework, it is important to note that the number of residues between the cysteines may vary. The final letter in the name indicates the order of discovery within that category.

For example, vc1a can be decoded to yield the following information: it belongs to the alpha pharmacological family, has be been isolated from Conus victoriae, has a type 1 disulfide framework (superfamily A) and was the first peptide to be discovered in this category. Please see table one below for an example representations of the different superfamily disulfide bond scaffolds.

Examples of cystine frameworks for the major super families of conotoxins.

Please note: In the figure of conotoxin cystine frameworks the A- and T- superfamily share a similar framework but differ in the disulfide linkage pattern. The A-superfamily disulfide pattern is also referred to as globular fold whereas the T-superfamily pattern is the ribbon isoform. (When synthesizing peptides without distinct protective groups for the cysteines both isoforms may be obtained.) The M-, O- and P-superfamily share the same disulfide linkage patterns but differ in their cystine framework, i.e. the spacing between the cysteine residues.

For each superfamily, subtypes may occur which differ in the number of residues between the cysteines, for example the αA 4/7 subtype has four residues after the second cysteine (CysII) and seven residues after the third cysteine (CysIII). In the T-superfamily spacing between CysIII and CysIV may be two residues as in MrIA (type III framework) or no residues as in Lt5a (type V framework). A more detailed overview on the conotoxin frameworks can be found here.

Conotoxins can also have N- and C-terminal extensions like the 4/7 αA-conotoxin GID which has a N-terminal extension of four amino acids.

FrameworkCystine pattern# cysteinesConnectivityReference
XXXIIIC-C-C-C-C-C-C-C-C-C-C-C12Pardos-Blas,J.R. et al. (2019) Marine drugs 17:453
XVIC-C-CC4Pi,C. et al. (2006) Genomics 88:809-819
ICC-C-C4I-III, II-IVGray,W.R. et al. (1981) J. Biol. Chem. 256:4734-4740
VCC-CC4I-III, II-IVWalker,C.S. et al. (1999) J. Biol. Chem. 274:30664-30671
XCC-C.[PO]C4I-IV, II-IIIBalaji,R.A. et al. (2000) J. Biol. Chem. 275:39516-39522
XIVC-C-C-C4I-III, II-IVMoller,C. et al. (2005) Biochemistry 44:15986-15996
IIICC-C-C-CC6Sato,S. et al. (1983) FEBS Lett. 155:277-280
VI/VIIC-C-CC-C-C6I-IV, II-V, III-VIOlivera,B.M. et al. (1984) Biochemistry 23:5087-5090
IXC-C-C-C-C-C6I-IV, II-V, III-VILirazan,M.B. et al. (2000) Biochemistry 39:1583-1588
XIC-C-CC-CC-C-C8I-IV, II-VI, III-VII, V-VIIIJimenez,E.C. et al. (2003) J. Neurochem. 85:610-621
VIIIC-C-C-C-C-C-C-C-C-C10England,L.J. et al. (1998) Science 281:575-578
XVIIC-C-CC-C-CC-C8Yuan,D.D. et al. (2008) Peptides 29:1521-1525
IICCC-C-C-C6Ramilo,C. et al. (1992) Biochemistry 31:9919-9926
XIIIC-C-C-CC-C-C-C8Aguilar,M.B. et al. (2005) Biochemistry 44:11130-11136
XVC-C-CC-C-C-C-C8Peng,C. et al. (2008) Peptides 29:985-991
XIIC-C-C-C-CC-C-C8Brown,M.A. et al. (2005) Biochemistry 44:9150-9159
XXVIIC-C-C-CCC-C-C8Jin,A.H. et al. (2015) Proc. Biol. Sci. 282
XVIIIC-C-CC-CC6Chen,J.S. et al. (1999) J Nat Toxins 8:341-349
XIXC-C-C-CCC-C-C-C-C10Chen,P. et al. (2008) Toxicon 52:139-145
XXC-CC-C-CC-C-C-C-C10Loughnan,M.L. et al. (2009) Biochemistry 48:3717-3729
XXIIC-C-C-C-C-C-C-C8Elliger,C.A. et al. (2011) Toxicon 57:311-322
XXICC-C-C-C-CC-C-C-C10Möller,C. and Marí,F. (2011) Biopolymers 96:158-165
XXIIIC-C-C-CC-C6Ye,M. et al. (2012) J Biol Chem 287:14973-14983
XXIVC-CC-C4Luo,S. et al. (2013) PLoS ONE 8
XXVC-C-C-C-CC6Aguilar,M.B. et al. (2013) Peptides 41:38-44
XXVIC-C-C-C-CC-CC8Bernáldez,J. et al. (2013) Mar Drugs 11:1188-1202
XXXIIC-CC-C-C-C6Kancherla,A.K. et al. (2015) ACS Chem. Biol. 10:1847-1860
XXIXCCC-C-CC-C-C8Bernáldez-Sarabia,J. et al. (2019) Toxins 11:128
XXXC-C-CCC-C-C-C-CC10Bernáldez-Sarabia,J. et al. (2019) Toxins 11:128
XXVIIIC-C-C-CC-C-C-C-C-C10Lu et al. (2017) Peptides, 94, pp.64-70 94:64-70
IVCC-C-C-C-C6I-V, II-III, IV-VIFainzilber,M. et al. (1995) Biochemistry 34:8649-8656

Cystine patterns used to define the cystine frameworks in ConoServer

SuperfamilyFrameworks# precursorsReference
A superfamilyI,II,IV,VI/VII,XIV,XXII 347 Santos,A.D. et al. (2004) J. Biol. Chem. 279:17596-17606
B1 superfamily 66 Puillandre,N. et al. (2012) J. Mol. Evol. 74:297-309
B2 superfamilyVIII 25 Dutertre,S. et al. (2013) Mol. Cell Proteomics 12:312-329
B3 superfamilyXXIV 1 Luo,S. et al. (2013) PLoS ONE 8
C superfamily 8 Puillandre,N. et al. (2012) J. Mol. Evol. 74:297-309
D superfamilyIV,XIV,XV,XX,XXIV,XXVIII 122 Loughnan,M.L. et al. (2009) Biochemistry 48:3717-3729
Divergent M---L-LTVAIX,VI/VII,XIV 11
E superfamilyXXII 9 Dutertre,S. et al. (2013) Mol. Cell Proteomics 12:312-329
F superfamily 18 Dutertre,S. et al. (2013) Mol. Cell Proteomics 12:312-329
G superfamilyXIII 1 Aguilar,M.B. et al. (2013) Peptides 41:17-20
G2 superfamilyIX,XXVII 20 Jin et al. (2017) Angewandte Chemie International Edition 56:14973-14976
H superfamilyVI/VII 21 Dutertre,S. et al. (2013) Mol. Cell Proteomics 12:312-329
I1 superfamilyVI/VII,XI,XXII 33 Jimenez,E.C. et al. (2003) J. Neurochem. 85:610-621
I2 superfamilyVI/VII,XI,XII,XIII,XIV 85 Buczek,O. et al. (2005) FEBS J. 272:4178-4188
I3 superfamilyVI/VII,XI 16 Yuan,D.D. et al. (2009) Peptides 30:861-865
Insulin superfamily 34 Ahorukomeye et al. (2019) eLife 8
J superfamilyXIV 47 Imperial,J.S. et al. (2006) Biochemistry 45:8331-8340
K superfamilyXXIII 6 Ye,M. et al. (2012) J Biol Chem 287:14973-14983
L superfamilyXIV,XXIV 28 Peng,C. et al. (2006) Peptides 27:2174-2181
M superfamilyI,II,III,IV,IX,VI/VII,XIV,XVI,XXXII 650 Corpuz,G.P. et al. (2005) Biochemistry 44:8176-8186
N superfamilyXV 5 Dutertre,S. et al. (2013) Mol. Cell Proteomics 12:312-329
O1 superfamilyI,IX,VI/VII,XII,XIV,XVI,XXIX 709 McIntosh,J.M. et al. (1995) J. Biol. Chem. 270:16796-16802
O2 superfamilyI,VI/VII,XII,XIV,XV,XVI 192 Zhangsun et al. (2006) Chem Biol Drug Des. 68:256-265
O3 superfamilyVI/VII,XVI 61 Zhangsun et al. (2006) Chem Biol Drug Des. 68:256-265
P superfamilyIX,XIV 22 Lirazan,M.B. et al. (2000) Biochemistry 39:1583-1588
Q superfamilyVI/VII,XVI 23 Lu,A. et al. (2014) Mol. Cell Proteomics 13:105-118
R superfamilyXIV 8
S superfamilyVIII,XXXIII 33 Liu,L. et al. (2008) Toxicon 51:1331-1337
T superfamilyI,V,X,XVI 280 Walker,C.S. et al. (1999) J. Biol. Chem. 274:30664-30671
U superfamilyVI/VII 9 Robinson,S.D. and Norton,R.S. (2014) Mar Drugs 12:6058-6101
V superfamilyXV 2 Peng,C. et al. (2008) Peptides 29:985-991
Y superfamilyVI/VII,XVII 4 Yuan,D.D. et al. (2008) Peptides 29:1521-1525
conodipine superfamily 5 Möller et al. (2019) Molecular & Cellular Proteomics 18:876-891

Superfamlies definition and framework usage in ConoServer.

alpha conotoxin Nicotinic acetylcholine receptors (nAChR) GI Gray,W.R. et al. (1981) J. Biol. Chem. 256:4734-4740
chi conotoxin Neuronal noradrenaline transporter MrIA, CMrVIA Sharpe,I.A. et al. (2001) Nat. Neurosci. 4:902-907
delta conotoxin Voltage-gated Na channels (agonist, delay inactivation) TxVIA Fainzilber,M. et al. (1991) Eur. J. Biochem. 202:589-595
epsilon conotoxin Presynaptic Ca channels or G protein-coupled presynaptic receptors TxVA Rigby,A.C. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96:5758-5763
gamma conotoxin Neuronal pacemaker cation currents (inward cation current) PnVIIA, TxVIIA Fainzilber,M. et al. (1998) Biochemistry 37:1470-1477
iota conotoxin Voltage-gated Na channels (agonist, no delayed inactivation) RXIA Buczek,O. et al. (2007) Biochemistry 46:9929-9940
kappa conotoxin Voltage-gated K channels (blocker) PVIIA Terlau,H. et al. (1996) Nature 381:148-151
mu conotoxin Voltage-gated Na channels (antagonist, blocker) GIIIA Cruz,L.J. et al. (1985) J. Biol. Chem. 260:9280-9288
omega conotoxin Voltage-gated Ca channels (blocker) GVIA Kerr,L.M. and Yoshikami,D. (1984) Nature 308:282-284
rho conotoxin Alpha1-adrenoceptors (GPCR) TIA Sharpe,I.A. et al. (2001) Nat. Neurosci. 4:902-907
sigma conotoxin Serotonin-gated ion channels 5-HT3 GVIIIA England,L.J. et al. (1998) Science 281:575-578
tau conotoxin Somatostatin receptor CnVA Petrel,C. et al. (2013) Biochem. Pharmacol.

Pharmacological definition used in ConoServer.