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(The FASEB Journal. 2001;15:1201-1205.)
© 2001 FASEB

Diversification of neurotoxins by C-tail ‘wiggling’: a scorpion recipe for survival

MICHAEL GUREVITZ1, DALIA GORDON, SHARON BEN-NATAN*, MICHAEL TURKOV and OREN FROY

Departments of Plant Sciences and
* Biochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel

1Correspondence: Department of Plant Sciences at the Faculty of Life Sciences, Tel-Aviv University, Britania Bldg., Rm. 506, Ramat-Aviv 69978, Tel-Aviv, Israel. E-mail: mamgur{at}post.tau.ac.il

ABSTRACT

The structure of bioactive surfaces of proteins is a subject of intensive research, yet the mechanisms by which such surfaces have evolved are largely unknown. Polypeptide toxins produced by venomous animals such as sea anemones, cone snails, scorpions, and snakes show multiple routes for active site diversification, each maintaining a typical conserved scaffold. Comparative analysis of an array of genetically related scorpion polypeptide toxins that modulate sodium channels in neuronal membranes suggests a unique route of toxic site diversification. This premise is based on recent identification of bioactive surfaces of toxin representative of three distinct pharmacological groups and a comparison of their 3-dimensional structures. Despite their similar scaffold, the bioactive surfaces of the various toxins vary considerably, but always coincide with the molecular exterior onto which the C-tail is anchored. Superposition of the toxin structures indicates that the C-tails diverge from a common structural start point, which suggests that the pharmacological versatility displayed by these toxins might have been achieved along evolution via structural reconfiguration of the C-tail, leading to reshaping of new bioactive surfaces.—Gurevitz, M., Gordon, D., Ben-Natan, S., Turkov, M., Froy, O. Diversification of neurotoxins by C-tail ‘wiggling’: a scorpion recipe for survival.


Key Words: toxic polypeptides • scorpion neurotoxin • bioactive surface

DIVERSIFICATION OF BIOACTIVITY IN TOXIC POLYPEPTIDES

PHYSICAL LIMITATION of various groups of animals such as sea anemones (Coelenterata), cone snails (Mollusca), scorpions (Arthropoda), and snakes (Chordata) has been compensated by developing venomous competence and predation based on ambush behavior. A mixture of deadly toxins that act simultaneously on multiple sites of the neuromuscular system and are capable of immobilizing a fast moving prey is injected to the target animal by a special stinging device. Extensive analysis of these toxins has shown that within a given animal group, the battery of functionally diverse toxic polypeptides evolved from a common ancestor (divergence evolution) (1 2 3 4 5 6) . However, recognition of similar target sites occurs in many instances by genetically unrelated toxins whose bioactive site has been formed independently (convergence evolution—e.g., potassium channel blockers such as {alpha}-dendrotoxins from the green mamba snake Dendroaspis angusticeps; charybdotoxin from the scorpion Leiurus quinquestriatus hebraeus; BgK sea anemone toxin from Bunodosoma granulifera; PVIIA {kappa}-conotoxin from Conus purpurascens) (reviewed in ref 6 ).

Divergent evolution of bioactive sites on conserved protein scaffolds has been shown for snake toxins, such as curarimimetics and fasciculins, that share a ‘three-fingered’ fold but act on distinct targets in the neuromuscular junction (nicotinic acetyl choline receptors or acetylcholine esterases, respectively; reviewed in ref 5 ). Similarly, snake dendrotoxins and bovine pancreatic trypsin inhibitors, which share a similar scaffold composed of two short helices and a two-stranded ß-sheet, target either various potassium channels or the active site of proteases, respectively (7 8 9) . In these examples, the bioactive sites are located at topographically unrelated regions of the conserved protein scaffolds. An alternative route of divergence has been adopted by cone snails that produce a large variety of small peptides (conotoxins), which are typified by a structural motif termed ‘cystine knot’ (10) and by their ability to block various types of ion channels. Diversification of conotoxins has been achieved via gene duplication, accelerated mutagenesis, insertion of unusual amino acid residues, and various posttranslational modifications, thereby generating a large number of variants with high specificity to various ion channel subtypes (2 , 11) . A unique route of diversification of bioactive sites has recently emerged from studies of scorpion toxins that produce different pharmacological effects on binding to neuronal sodium channels (12 13 14 15) .

SCORPION NEUROTOXINS AFFECTING SODIUM CHANNELS

Scorpions, whose senses are undeveloped, have survived more than 350 million years with no detectable changes in their anatomy due to their efficient, dynamic machinery for the production and diversification of neurotoxins. They produce a wide array of structurally conserved toxic polypeptides capable of poisoning animals of vast phylogenetic origin (16) . In particular, toxins affecting voltage-gated sodium channels exert the utmost impact on both vertebrates and invertebrates (15 , 16) . Despite general conservation in channel structure and function, these toxins exhibit diverse binding properties to sodium channels in various excitable tissues, indicating differences in receptor sites (15) . The ever-changing receptor sites along evolution required structural reshaping of the toxic ligands, a task fulfilled successfully by scorpions of the family Buthidae. The conservation of toxin 3-dimensional structure (3-D) (15 , 17) alongside an inevitable demand for diverse bioactive sites has posed competing pressures on the evolution of these polypeptides.

Diverse pharmacology
Scorpion toxins affecting sodium channels are 61–76 amino acid-long polypeptides that have been divided into two major classes, {alpha} and ß, according to their mode of action and binding properties (15 , 16) . These two classes induce different modulation of the sodium current by binding at two distinct receptor sites on the sodium channels. {alpha}-Toxins inhibit inactivation of the sodium current by binding to receptor site 3 and are subdivided into distinct pharmacological groups according to their preference for phylogenetically distinct target sites (12 , 15) . Conversely, ß-toxins shift the activation of the sodium current to a more negative membrane potential by binding to receptor site 4 (12 , 13) . Most {alpha}- and ß-toxins affect mammalian and insect sodium channels with various affinities. However, two pharmacologically distinct toxin groups, excitatory and depressant, which affect exclusively sodium channels of insects, have been characterized (18 , 20) . Both groups induce opposite effects on the sodium current by affecting the activation process of the sodium channel (18 , 20) and bind to distinct yet closely related receptor sites (21) . For these reasons and due to their capability to compete with ß-toxins for the receptor binding site, excitatory and depressant toxins have been suggested to belong to the ß class (15) . Sequence comparison among the various groups reveals ~30% similarity, whereas the toxins within each group may differ up to 50% (15 , 17 ; Fig. 1 ).



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  		Figure 1. Sequence alignment of representative sodium channel modifiers from scorpion venoms. Alignment is based on published data (15 , 20 , 30) . Dashes indicate gaps; asterisks designate {alpha}-amidation of carboxy-terminal residues. The conserved (solid lines) and the nonconserved (dashed line) disulfide bridges are depicted at the bottom. B, ß-strand; T, turn; H, {alpha}-helix. AaH, Androctonus australis Hector; Bj, Buthotus judaicus; Bom, Buthus occitanus mardochei: Lqh, Leiurus quinquestriatus hebraeus; Lqq, Leiurus quinquestriatus quinquestriatus; Cn, Centruroides noxius; Ts, Tityus serrulatus.

Conservation of 3-D structure
The 3-D structure of several {alpha}-toxins has been known for more than a decade (15 , 17 , 22) , but it is only recently that the structure of an anti-insect selective excitatory toxin (23) and that of an anti-mammalian ß-toxin (24) have been solved. In addition, the resemblance between depressant and ß-toxins in sequence, neurophysiological action, and competition for receptor binding site (15) permits structural modeling of depressant toxins. Despite their diverse bioactivity and sequence, all the above toxins share a common scaffold comprising a {alpha}-helix and a three-stranded anti-parallel ß-sheet ({alpha}/ß scaffold) that occupies most of their globular structure. The {alpha}/ß scaffold is stabilized by three spatially conserved disulfide bridges and a fourth bridge is conserved in all but the excitatory toxins (23 , 25) (Fig. 1) . Moreover, all these toxins contain a solvent-exposed patch of aromatic and hydrophobic residues, coined ‘conserved hydrophobic surface’, whose function is still unknown. The mutual disposition of the {alpha}-helix and the ß-sheet in all toxins is similar. However, the carboxy-terminal stretch and the regions connecting the secondary structure elements differ in the various toxins (15) .

Similarity in genomic organization
Recently, the similar genomic organization of all the aforementioned toxin genes has been shown. All genes contain A+T-rich introns that split, at a conserved location, an amino acid codon of the signal sequence. The introns vary in length and sequence, but display identical boundaries and contain T runs downstream of a putative conserved branch point (3) .

Hence, on the basis of three levels of comparison (function, structure, and gene organization), it has been suggested that all scorpion neurotoxins affecting sodium channels have diverged from a common ancestor (3 , 4) . Nonetheless, all descendants show vast sequence diversity, reflecting a high degree of inherent permissiveness to amino acid substitutions without detrimental deformation of the overall fold. To envisage a mechanism by which novel bioactive sites have evolved, a comparison of toxin structures and bioactive surfaces is required.

IDENTIFICATION OF BIOACTIVE SURFACES AND STRUCTURE COMPARISON

An efficient system for production of recombinant toxins in milligram amounts (20 , 26 , 27) has enabled structure determination (23 , 28) and genetic dissection (20 , 29) of two toxins that represent distinct pharmacological classes: Lqh{alpha}IT from the {alpha} class and Bj-xtrIT from the ß class. Seven residues organized in a belt shape surrounding the toxin molecule are important for bioactivity of Lqh{alpha}IT as their substitution reduced toxicity at least fivefold compared to the unmodified toxin (29 and Fig. 2 ). Three of them—Arg58, Val59, and Lys62—belong to the C-tail; the side chains of the rest (Lys8, Tyr10, Phe17, and Arg18) are located on the outer surface of the {alpha}/ß scaffold (Fig. 2 , bottom right). In the excitatory toxin Bj-xtrIT, substitution of Asp55, Asp70, Ser76, Asn28, and Tyr36 reduced toxicity more than fivefold whereas substitution of Ile73 and Ile74 had a much larger effect of 100-fold (20 and Fig. 2 , bottom left). These analyses highlight residues important for bioactivity that are contributed by the C-tail as well as by the surface vicinal to its disulfide anchoring site on the molecule exterior.



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  		Figure 2. Superposition of the C{alpha} backbone of scorpion toxins affecting sodium channels (top). Four toxins representing distinct pharmacological groups are delineated by ribbons: the alpha toxin Lqh{alpha}IT (28) , the beta toxin Cn2 (24) , and the excitatory toxin Bj-xtrIT (23) have blue, magenta, and red C-tails, respectively. The last three residues could not be seen in the X-ray structure of Bj-xtrIT, but most likely cover residue 38 in the center of the bioactive surface (23) . A model of a depressant toxin, LqhIT2, is presented with a green C-tail (the model was constructed by alignment to Cn2 using the Modeller and Homology modules of Insight II, MSI, Cambridge, UK). The {alpha}-helix and ß-strands are highlighted (barrel and arrows, respectively). The three conserved disulfide bridges are depicted in yellow lines; the fourth disulfide bridge is shown by yellow balls and sticks. The putative bioactive surfaces of Lqh{alpha}IT (bottom right), LqhIT2 (bottom center), and Bj-xtrIT (bottom left) are highlighted by balls and sticks in blue, green, and red, respectively. The carbon backbone of the C-tail of each molecule is shown in the corresponding color and identical orientation as above. The stereo display of all structures was constructed using Insight II (MSI, Cambridge, UK).

Superposition of the C{alpha} backbones of the {alpha}-toxin Lqh{alpha}IT (28) , ß-toxin Cn2 (24) , and excitatory toxin Bj-xtrIT (23) highlight the 180° positional shift of the C-tail of Bj-xtrIT and its fourth disulfide bridge relative to the other toxins (Figs. 1 and 2) . The orientation of the bioactive surface with respect to the {alpha}/ß scaffold differs between Bj-xtrIT and Lqh{alpha}IT and seems to correspond to the molecular exterior onto which the C-tail is anchored. To verify this hypothesis, we analyzed LqhIT2, a toxin representative of the depressant group that, unlike the excitatory and {alpha}-toxins, decreases the sodium current in cockroach neuronal membranes (15 , 19) . Mutagenesis of Asn58 and Gly61 of the C-tail, as well as Asp8, Lys11, Lys26 of its vicinal surface, reduced the toxicity of LqhIT2 more than fivefold (Fig. 2 and unpublished results). These residues form a bioactive surface encompassing the fourth disulfide bridge that anchors the C-tail onto the molecule (Fig. 2 , bottom center).

From these analyses, it has become evident that the bioactive surface of each toxin examined thus far includes the distal region of the C-tail and spatially vicinal residues. Furthermore, substitution of the residues contributed by the distal part of the C-tail had the utmost effect on bioactivity.

A comparison of the structural models of Lqh{alpha}IT, Cn2, Bj-xtrIT, and LqhIT2 accentuates the difference in the spatial arrangement of the C-tail (23 , 24 , 28) (Fig. 2) . As implicated from several toxin solution structures, the carboxy-terminal region is dynamic despite its anchoring onto the polypeptide scaffold by the fourth disulfide bridge (17 , 28 , 30 , 31) . In contrast to the spatial conservation of this bridge in {alpha}-, ß-, and depressant toxins, its position in excitatory toxins is different (23 , 25) (Fig. 1) but with no structural perturbation of the conserved {alpha}/ß scaffold (23 and Fig. 2 ). Superposition of the four toxins explicitly indicates a common start point after the third ß-strand, from which all C-tails diverged (Fig. 2) . Hence, all toxins constitute on the one hand a rigid {alpha}/ß scaffold and, on the other hand, a highly variable carboxy-terminal tail confined mainly by the fourth disulfide bridge (Fig. 2) .

DIVERSIFICATION OF BIOACTIVE SURFACES

These observations illuminate a putative evolutionary route for diversification of bioactive surfaces possibly in an accelerated manner. In this scenario, the carboxy-terminal region, starting after the third ß-strand and protruding out of the {alpha}/ß scaffold, has undergone structural rearrangements as a result of amino acid substitutions that led to the formation of new molecular exteriors. The evolutionary ‘wiggling’ of the C-tail has been confined by the fourth disulfide bridge, whose position in excitatory toxins is remote from the conserved position in all other toxins (Fig. 2) . The shift in position in excitatory toxins has most likely occurred in parallel to the insertion of an additional {alpha}-helical module (23) serving presumably as a molecular ‘lever’ facilitating the structural alteration. Thus, we hypothesize that alterations in a short hypervariable region, having a limited degree of structural freedom due to the fourth disulfide bridge, induced the formation of a variety of bioactive surfaces. This process may have occurred in parallel to the evolutionary changes of target sites in sodium channels. The molecular surfaces exerting novel bioactivities with an advantage for predation or defense have most likely become the progenitors of the existing pharmacological groups, e.g., alpha and its subgroups, beta, excitatory, and depressant toxins. Apparently, additional alterations of residues in these surfaces enabled increase in binding affinity to the various receptor sites. The vast genetic polymorphism of all scorpion neurotoxins (3) suggests that the evolutionary process has not ceased and that the ‘pharmaceutical factory’ in scorpion venom glands still seeks new bioactive sites.

From a mechanistic point of view, this scorpion toxin model is reminiscent of the diversification of antigen binding sites that occurs in the immune system. The variable light and heavy chains of antibodies constitute two domains, a hypervariable unit comprising six complementarity-determining regions (CDRs) and a framework region exhibiting fewer variations. The framework region serves as a scaffold for structural disposition of the CDR loops of the heavy and the light chains. Superposition of all antibody structures reveals differences in CDR loop orientation, length, and amino acid composition, thereby generating a wide spectrum of specificities (32) .

Although scorpion toxins and antibodies are by no means comparable, it is interesting to observe a strategic commonality in their diversification where only a section of the protein displays structural variability, thereby inducing changes in an interactive molecular face to cope with ever-changing targets at minimal energy expense.

In summary, comparative analysis of the structure, bioactive surface, and pharmacology of scorpion toxins affecting sodium channels sheds a new light on a putative evolutionary mechanism of bioactive site formation. It may further aid in the prediction of unknown toxic surfaces concentrating on the molecular surface around the C-tail anchoring site and perhaps facilitate the design of novel effectors of sodium channels using the highly conserved skeleton of scorpion toxins (33) .

ACKNOWLEDGMENTS

Our research was supported by grants IS-2901–97C from BARD, The United States-Israel Binational Agricultural Research & Development; 466/97 from The Israel Academy of Sciences and Humanities; 131-1037-98 from DIARP, a Joint Dutch-Israeli Agricultural Research Program; and a fund from the Biotechnology Infrastructure Program of the Israeli Ministry of Science, 1998.

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