Conus ~ VenomZone

Cone snails are marine gastropod mollusks that are found in reef environments throughout the world. They prey upon other marine organisms such as annelids and polychaetes (vermivorous), mollusks (molluscivorous) or fish (piscivorous). To capture and immobilize their prey, they developed in their venom a variety of toxins (or conotoxins also called conopeptides) that inhibit a range of membrane bound receptors and ion channels. Even cone snails only feed of marine animals their toxins are also active against mammalian channels/receptors, making them valuable tools in medical research.

Each cone snail venom may contain up to 200 peptides (Olivera, 2006, Terlau and Olivera, 2004) and given that there are over 500 cone snail species (Olivera et al., 2012), the library of bioactive peptides is huge (about 10,000).

These bioactive peptides have been grouped structurally into superfamilies on the basis of similarities in precursor signal peptide sequences and the cysteine patterns of conotoxin mature peptide regions (cysteine frameworks), and in pharmacological families based on the specificity to molecular targets.

Conus textile (Image from Wikipedia / licensed under Creative Commons).

The table below shows the classification of conotoxins based on the pharmacological family.

Pharmacological family	UniProtKB entries	Activity (impairs function of)
Alpha-conotoxin		Nicotinic acetylcholine receptor (nAChR)
Chi-conotoxin		Neuronal noradrenaline transporter
Delta-conotoxin		Voltage-gated Na channel (agonist, delay inactivation)
Epsilon-conotoxin		Presynaptic Ca channel or G protein-coupled presynaptic receptor
Gamma-conotoxin		Neuronal pacemaker cation current (inward cation current)
Iota-conotoxin		Voltage-gated Na channel (agonist, no delayed inactivation)
Kappa-conotoxin		Voltage-gated K channel (blocker)
Mu-conotoxin		Voltage-gated Na channel (antagonist, blocker)
MuO-conotoxin		Voltage-gated Na channel (antagonist, voltage-gating modifier)
Omega-conotoxin		Voltage-gated Ca channel (blocker)
Rho-conotoxin		Alpha1-adrenoceptor (GPCR)
Sigma-conotoxin		Serotonin-gated ion channel (GPCR)
Conantokin		N-Methyl D-aspartate (NMDA) receptor

The table below shows the classification of conotoxins based on the cysteine framework.

Cysteine framework	number of cysteines	Cysteine pattern
I	4	CC-C-C
		α3/2 (CCxxxCxxC)
		α3/5 (CCxxxCxxxxxC)
		α4/2 (CCxxxxCxxC)
		α4/3 (CCxxxxCxxxC)
		α4/4 (CCxxxxCxxxxC)
		α4/5 (CCxxxxCxxxxxC)
		α4/6 (CCxxxxCxxxxxxC)
		α4/7 (CCxxxxCxxxxxxxC)
		α4/8 (CCxxxxCxxxxxxxxC)
		α5/5 (CCxxxxCxxxxxxxxC)
		α5/8 (CCxxxxxCxxxxxxxxC)
		α9/4 (CCxxxxxxxxxCxxxxC)
II	6	CCC-C-C-C
III	6	CC-C-C-CC
IV	6	CC-C-C-C-C
V	4	CC-CC
VI/VII	6	C-C-CC-C-C
VIII	10	C-C-C-C-C-C-C-C-C-C
IX	6	C-C-C-C-C-C
X	4	CC-CX[hydroxyPro]C
XI	8	C-C-CC-CC-C-C
XII	8	C-C-C-C-CC-C-C
XIII	8	C-C-C-CC-C-C-C
XIV	4	C-C-C-C
XV	8	C-C-CC-C-C-C-C
XVI	4	C-C-CC
XVII	8	C-C-CC-C-CC-C
XVIII	6	C-C-CC-CC
XIX	10	C-C-C-CCC-C-C-C-C
XX	10	C-CC-C-CC-C-C-C-C
XXI	10	CC-C-C-C-CC-C-C-C
XXII	8	C-C-C-C-C-C-C-C
XXIII	6	C-C-C-CC-C
XXIV	4	C-CC-C
XXV	6	C-C-C-C-CC
XXVI	8	C-C-C-C-CC-CC
XXVII	8	C-C-C-CCC-C-C
XXVIII	10	C-C-C-CC-C-C-C-C-C
XXIX	8	CCC-C-CC-C-C
XXX	6	C-C-CCC-C-C-C-CC
XXXII	6	C-CC-C-C-C
special cases
conantokin, contulakin, conorfamide, conomap, conophan, conolysin	0	no cysteine
conantokin, contulakin, conopressin, contryphan	2	C-C
conkunitzin	4	C-C-C-C
homodimer	5	C-C-C-C-C
	6	C-C-C-CC-C
	7	C-C-C-CC-C-C
	8	CCC-C-CC-C-C
	8	C-C-CCC-C-C-C
	8	C-C-C-C-C-C-CC
	9	C-C-C-C-C-C-C-C-C
	10	C-C-CC-CC-C-C-C-C
	13	CC-CC-C-C-C-CC-C-C-C-C

The table below shows the classification of conotoxins based on similarities in precursor signal peptide sequences.

Protein family or Superfamily in UniProtKB	UniProtKB entries
Conotoxin A superfamily
Conotoxin B superfamily
Conotoxin C superfamily
Conotoxin D superfamily
Conotoxin E superfamily
Conotoxin F superfamily
Conotoxin G superfamily
Conotoxin G2 superfamily
Conotoxin H superfamily
Conotoxin J superfamily
Conotoxin I1 superfamily
Conotoxin I2 superfamily
Conotoxin I3 superfamily
Conotoxin K superfamily
Conotoxin L superfamily
Conotoxin M superfamily
Conotoxin N superfamily
Conotoxin O1 superfamily
Conotoxin O2 superfamily
Conotoxin O3 superfamily
Conotoxin P superfamily
Conotoxin S superfamily
Conotoxin R superfamily
Conotoxin T superfamily
Conotoxin V superfamily
Conotoxin Y superfamily
Conotoxin NSf-1 superfamily


CRISP family
FARP (FMRFamide related peptide) family
NPY family
Venom Kunitz-type family
Phospholipase A2 family
Vasopressin/oxytocin family
Porin family

SUPERFAMILY:	Conoidea
Family:	Conidae
Genus:	Conus
Species:	californicus
Species:	consors
Species:	litteratus
Species:	ventricosus
Species:	textile

Conus

Venom protein entries in UniProtKB/Swiss-Prot

Actinoporin family, Conoidea subfamily

ConoGAY family

Conophan family

Conotoxin A superfamily

Conotoxin B superfamily

Conotoxin B2 family

Conotoxin C superfamily

Conotoxin D superfamily

Conotoxin E superfamily

Conotoxin F superfamily

Conotoxin G2 superfamily, 1 family

Conotoxin H superfamily

Conotoxin I1 superfamily

Conotoxin I2 superfamily

Conotoxin I3 superfamily

Conotoxin J superfamily

Conotoxin K superfamily

Conotoxin L superfamily

Conotoxin M superfamily

Conotoxin M superfamily, Conopeptide Y family

Conotoxin N superfamily

Conotoxin O1 superfamily

Conotoxin O2 superfamily

Conotoxin O3 superfamily

Conotoxin P superfamily

Conotoxin Q superfamily

Conotoxin R superfamily

Conotoxin S superfamily

Conotoxin T superfamily

Conotoxin V superfamily

Conotoxin Y superfamily

CRISP family

E superfamily

F superfamily

FARP (FMRFamide related peptide) family

Glycoprotein hormones subunit alpha family

Glycoprotein hormones subunit beta family

Glycosyl hydrolase 56 family

I1 superfamily

Insulin family

Not in a family

NPY family

O1 superfamily

O2 superfamily, Contryphan family

Phospholipase A2 family, Group IX subfamily

Vasopressin/oxytocin family

Venom Kunitz-type family