Irditoxin

Irditoxin is a three-finger toxin (3FTx) protein found in the venom of the brown tree snake (Boiga irregularis) and likely in other members of the genus Boiga. It is a heterodimer composed of two distinct protein chains, each of the three-finger protein fold, linked by an intermolecular disulfide bond. This structure is unusual for 3FTx proteins, which are most commonly monomeric.[1][2][3]

Structure of irditoxin, with subunit A in blue and subunit B in orange. In each subunit, intramolecular disulfide bonds are shown as yellow sticks. The intramolecular disulfide bond at the dimer interface is shown as green and yellow spheres.[1]
Irditoxin subunit A
Identifiers
OrganismBoiga irregularis
Symbol3NBA
PDB2H7Z
UniProtA0S864
Irdixotin subunit B
Identifiers
OrganismBoiga irregularis
Symbol3NBB
PDB2H7Z
UniProtA0S865

Structure

Three-finger toxin (3FTx) proteins canonically consist of approximately 60-80 amino acid residues that assume a structure with three "finger"-like beta strand-containing loops projecting from a core stabilized by four intramolecular disulfide bonds. Irditoxin is a covalent heterodimer in which two subunits are linked by an intermolecular disulfide bond. Each subunit is of the three-finger toxin (3FTx) protein superfamily and is most closely related to the "non-conventional" 3FTx subclass, characterized by the presence of an additional disulfide bond in the first of the canonical three "finger" loops. Each subunit thus contains 11 cysteine residues: the eight canonical residues that form the core disulfide bonds, the two in the first loop forming the non-conventional disulfide, and the one that forms the dimeric linkage. Irditoxin subunits A and B are 75 and 77 amino acid residues long, respectively, and each possess a seven-residue extension with a pyroglutamic acid post-translational modification at the N-terminus.[1][2]

Irditoxin's structure is highly unusual within the 3FTx superfamily.[2] Most 3FTx proteins are monomers. The best-studied exception is kappa-bungarotoxin, a non-covalent homodimer with a very different protein-protein interaction surface;[2] the recently described alpha-cobratoxin also forms both covalent homodimers and low-abundance covalent heterodimers with other 3FTx proteins found in monocled cobra (Naja kaouthia) venom.[4] It is as yet unclear how irditoxin's two subunits contribute to its biological activities.[2]

Function

Irditoxin is an abundant protein in the venom of the brown tree snake and accounts for about 10% of the protein found in venom samples of brown treesnakes collected from Guam, where they are an invasive species. Irditoxin's toxic effects are highly species-dependent; in laboratory tests, it is highly toxic to lizards and birds but not to mammals. Although the molecular mechanism of toxicity is not clear, irditoxin produces robust post-synaptic blockade of signaling in the avian neuromuscular junction.[1]

Discovery and nomenclature

Irditoxin was first described in 2009 after isolation from samples of venom from the brown tree snake. Its name is a contraction of "B. irregularis dimeric toxin".[1] Other Boiga species, and possibly other colubrid snakes, likely possess homologous proteins.[5]:18

References
  1. Pawlak J, Mackessy SP, Sixberry NM, Stura EA, Le Du MH, Ménez R, Foo CS, Ménez A, Nirthanan S, Kini RM (February 2009). "Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity". FASEB Journal. 23 (2): 534–45. doi:10.1096/fj.08-113555. PMID 18952712.
  2. Kini RM, Doley R (November 2010). "Structure, function and evolution of three-finger toxins: mini proteins with multiple targets". Toxicon. 56 (6): 855–67. doi:10.1016/j.toxicon.2010.07.010. PMID 20670641.
  3. Doley R, Kini RM (September 2009). "Protein complexes in snake venom". Cellular and Molecular Life Sciences. 66 (17): 2851–71. doi:10.1007/s00018-009-0050-2. PMID 19495561.
  4. Osipov AV, Rucktooa P, Kasheverov IE, Filkin SY, Starkov VG, Andreeva TV, Sixma TK, Bertrand D, Utkin YN, Tsetlin VI (February 2012). "Dimeric α-cobratoxin X-ray structure: localization of intermolecular disulfides and possible mode of binding to nicotinic acetylcholine receptors". The Journal of Biological Chemistry. 287 (9): 6725–34. doi:10.1074/jbc.M111.322313. PMC 3307301. PMID 22223648.
  5. Mackessy SP (2010-01-01). Handbook of venoms and toxins of reptiles. CRC Press. ISBN 9781420008661. OCLC 757355711.
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