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Target-Driven Evolution of Scorpion Toxins.

Zhang S, Gao B, Zhu S - Sci Rep (2015)

Bottom Line: By using maximum-likelihood models of codon substitution, we analyzed molecular adaptation in scorpion sodium channel toxins from a specific species and found ten positively selected sites, six of which are located at the core-domain of scorpion α-toxins, a region known to interact with two adjacent loops in the voltage-sensor domain (DIV) of sodium channels, as validated by our newly constructed computational model of toxin-channel complex.This work presents an example of atypical co-evolution between animal toxins and their molecular targets, in which toxins suffered from more prominent selective pressure from the channels of their competitors.Our discovery helps explain the evolutionary rationality of gene duplication of toxins in a specific venomous species.

View Article: PubMed Central - PubMed

Affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects &Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China.

ABSTRACT
It is long known that peptide neurotoxins derived from a diversity of venomous animals evolve by positive selection following gene duplication, yet a force that drives their adaptive evolution remains a mystery. By using maximum-likelihood models of codon substitution, we analyzed molecular adaptation in scorpion sodium channel toxins from a specific species and found ten positively selected sites, six of which are located at the core-domain of scorpion α-toxins, a region known to interact with two adjacent loops in the voltage-sensor domain (DIV) of sodium channels, as validated by our newly constructed computational model of toxin-channel complex. Despite the lack of positive selection signals in these two loops, they accumulated extensive sequence variations by relaxed purifying selection in prey and predators of scorpions. The evolutionary variability in the toxin-bound regions of sodium channels indicates that accelerated substitutions in the multigene family of scorpion toxins is a consequence of dealing with the target diversity. This work presents an example of atypical co-evolution between animal toxins and their molecular targets, in which toxins suffered from more prominent selective pressure from the channels of their competitors. Our discovery helps explain the evolutionary rationality of gene duplication of toxins in a specific venomous species.

No MeSH data available.


Divergence rates (ω) for each site of VSD from both predators and prey of scorpions.The ω values are calculated on Selecton under M8a model. For clarity, all sequences are numbered according to rNav1.2. Secondary structural elements are extracted from the rNav1.2 VSD model29 where α-helices are shown as cylinder, two extracellular loops involved in toxin binding as lines in red, and the intracellular loop in grey.
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f4: Divergence rates (ω) for each site of VSD from both predators and prey of scorpions.The ω values are calculated on Selecton under M8a model. For clarity, all sequences are numbered according to rNav1.2. Secondary structural elements are extracted from the rNav1.2 VSD model29 where α-helices are shown as cylinder, two extracellular loops involved in toxin binding as lines in red, and the intracellular loop in grey.

Mentions: Firstly, we used the same ML models of codon substitution to test selective pressure in the VSD from the four different lineages (birds, lizards, mammals and insects) and, unexpectedly, we detected no any signals for their adaptive sequence evolution. The MLEs under M0 suggest that average ω ratios for overall sequence pairs in these lineage ranged from 0.02 to 0.09, far smaller than 0.85 in the toxin gene (Tables 1, 2, 3, 4, 5), indicating strong purifying selection on the VSD, consistent with the prediction of M2a and M8 that detected no sites evolved by positive selection. Although M8 fits the data better than M7 in the bird Nav channel (2Δl = 11.6, 0.002 < p < 0.005), the extra class of sites (3%) has a ωs = 1 rather than >1 (Table 2). In the mammalian and insect Nav channels, the MLEs under M8 gave ωs > 1, but their proportion (p1) equals 0 (Tables 4 and 5). Hence, no site was positively selected in these genes. Comparison of the log likelihood values revealed that M0 fits the data worse than other models in all the lineages (Tables 2, 3, 4, 5), supporting the presence of variable selective pressure among sites of the VSD. We therefore calculated ω values for each site in the VSD of different lineages by Selecton, a server for detecting evolutionary forces at a single amino-acid site, under M8a33. This model is a variation of M8 with the ωs of the extra class sites set to 1 other than >1 in M81834 and thus suitable for testing purifying and neutral selection in each site (0 < ω ≤ 1). As shown in Fig. 4, each site has different evolutionary rates and in particular a significantly higher ω was observed in sites belonging to the two extracellular loops (LDIVS1-S2 and LDIVS3-S4) than those in their respective adjacent helical segments in the predators (Fig. 4). In insects, a similar case was also observed in LDIVS1-S2. The elevated evolutionary rates in the loops suggest they are under lower selective constraints than the helices, evidence for relaxed purifying selection. This could be ascribed to the distinct physiological role of VSD (DIV) in the Nav channel fast inactivation, in which the helices are structurally and functionally important elements35 and they thus are expected to be constrained by stronger purifying selection to maintain their sequence and structural conservation. On the contrary, the two loops can tolerate more amino-acid substitutions in the absence of functional constraint.


Target-Driven Evolution of Scorpion Toxins.

Zhang S, Gao B, Zhu S - Sci Rep (2015)

Divergence rates (ω) for each site of VSD from both predators and prey of scorpions.The ω values are calculated on Selecton under M8a model. For clarity, all sequences are numbered according to rNav1.2. Secondary structural elements are extracted from the rNav1.2 VSD model29 where α-helices are shown as cylinder, two extracellular loops involved in toxin binding as lines in red, and the intracellular loop in grey.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595728&req=5

f4: Divergence rates (ω) for each site of VSD from both predators and prey of scorpions.The ω values are calculated on Selecton under M8a model. For clarity, all sequences are numbered according to rNav1.2. Secondary structural elements are extracted from the rNav1.2 VSD model29 where α-helices are shown as cylinder, two extracellular loops involved in toxin binding as lines in red, and the intracellular loop in grey.
Mentions: Firstly, we used the same ML models of codon substitution to test selective pressure in the VSD from the four different lineages (birds, lizards, mammals and insects) and, unexpectedly, we detected no any signals for their adaptive sequence evolution. The MLEs under M0 suggest that average ω ratios for overall sequence pairs in these lineage ranged from 0.02 to 0.09, far smaller than 0.85 in the toxin gene (Tables 1, 2, 3, 4, 5), indicating strong purifying selection on the VSD, consistent with the prediction of M2a and M8 that detected no sites evolved by positive selection. Although M8 fits the data better than M7 in the bird Nav channel (2Δl = 11.6, 0.002 < p < 0.005), the extra class of sites (3%) has a ωs = 1 rather than >1 (Table 2). In the mammalian and insect Nav channels, the MLEs under M8 gave ωs > 1, but their proportion (p1) equals 0 (Tables 4 and 5). Hence, no site was positively selected in these genes. Comparison of the log likelihood values revealed that M0 fits the data worse than other models in all the lineages (Tables 2, 3, 4, 5), supporting the presence of variable selective pressure among sites of the VSD. We therefore calculated ω values for each site in the VSD of different lineages by Selecton, a server for detecting evolutionary forces at a single amino-acid site, under M8a33. This model is a variation of M8 with the ωs of the extra class sites set to 1 other than >1 in M81834 and thus suitable for testing purifying and neutral selection in each site (0 < ω ≤ 1). As shown in Fig. 4, each site has different evolutionary rates and in particular a significantly higher ω was observed in sites belonging to the two extracellular loops (LDIVS1-S2 and LDIVS3-S4) than those in their respective adjacent helical segments in the predators (Fig. 4). In insects, a similar case was also observed in LDIVS1-S2. The elevated evolutionary rates in the loops suggest they are under lower selective constraints than the helices, evidence for relaxed purifying selection. This could be ascribed to the distinct physiological role of VSD (DIV) in the Nav channel fast inactivation, in which the helices are structurally and functionally important elements35 and they thus are expected to be constrained by stronger purifying selection to maintain their sequence and structural conservation. On the contrary, the two loops can tolerate more amino-acid substitutions in the absence of functional constraint.

Bottom Line: By using maximum-likelihood models of codon substitution, we analyzed molecular adaptation in scorpion sodium channel toxins from a specific species and found ten positively selected sites, six of which are located at the core-domain of scorpion α-toxins, a region known to interact with two adjacent loops in the voltage-sensor domain (DIV) of sodium channels, as validated by our newly constructed computational model of toxin-channel complex.This work presents an example of atypical co-evolution between animal toxins and their molecular targets, in which toxins suffered from more prominent selective pressure from the channels of their competitors.Our discovery helps explain the evolutionary rationality of gene duplication of toxins in a specific venomous species.

View Article: PubMed Central - PubMed

Affiliation: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects &Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China.

ABSTRACT
It is long known that peptide neurotoxins derived from a diversity of venomous animals evolve by positive selection following gene duplication, yet a force that drives their adaptive evolution remains a mystery. By using maximum-likelihood models of codon substitution, we analyzed molecular adaptation in scorpion sodium channel toxins from a specific species and found ten positively selected sites, six of which are located at the core-domain of scorpion α-toxins, a region known to interact with two adjacent loops in the voltage-sensor domain (DIV) of sodium channels, as validated by our newly constructed computational model of toxin-channel complex. Despite the lack of positive selection signals in these two loops, they accumulated extensive sequence variations by relaxed purifying selection in prey and predators of scorpions. The evolutionary variability in the toxin-bound regions of sodium channels indicates that accelerated substitutions in the multigene family of scorpion toxins is a consequence of dealing with the target diversity. This work presents an example of atypical co-evolution between animal toxins and their molecular targets, in which toxins suffered from more prominent selective pressure from the channels of their competitors. Our discovery helps explain the evolutionary rationality of gene duplication of toxins in a specific venomous species.

No MeSH data available.