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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.


Sequence logos.(A) Nav channel VSDs from birds, lizards, mammals and insects; (B) Scorpion α-toxins. Each logo consists of stacks of letters and the overall height of each stack indicates the sequence conservation at that position (measured in bits). The height of symbols within the stack reflects the relative frequency of the corresponding amino acid at that position39. Loops involved in toxin-channel interaction are boxed in orange in both toxins and channels; and positions of amino acids implicated in binding of rNav1.2 to Lqh225 are labeled by asterisks.
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f6: Sequence logos.(A) Nav channel VSDs from birds, lizards, mammals and insects; (B) Scorpion α-toxins. Each logo consists of stacks of letters and the overall height of each stack indicates the sequence conservation at that position (measured in bits). The height of symbols within the stack reflects the relative frequency of the corresponding amino acid at that position39. Loops involved in toxin-channel interaction are boxed in orange in both toxins and channels; and positions of amino acids implicated in binding of rNav1.2 to Lqh225 are labeled by asterisks.

Mentions: Given the extensive existence of co-evolution between proteins and their interaction partners (e.g. ligand-receptor pairs)3738, the lack of matched PSSs in the toxin-bound region of Nav channels is puzzling as strong positive selection signals exist in the channel-bound region of the toxins (Fig. 3). To address this puzzling, we further analyzed sequence conservation in the VSD using WebLogo, a web-based application designed to make the generation of sequence logos39. The results indicate that the two loops (LDIVS1-S2; LDIVS3-S4) are highly variable in birds, lizards and mammals relative to their adjacent transmembrane helices (S1–S4) that show more conservation (Fig. 6A). In insects, more variability was also found in LDIVS1-S2. In parallel, we calculated the sequence logo of the toxin family, confirming the variability of the two positively selected loops (B- and J-loop) (Fig. 6B). The evolutionary variability of the toxin-bound region in VSDs of the Nav channels is further confirmed by ConSurf, an algorithmic tool for the identification of variable and conserved regions in proteins by surface mapping of phylogenetic information40. As shown in Fig. 7A, BmKM1 binds to the two variable loops of the mammalian VSDs primarily via its PSSs (shown in blue). In the other two vertebrate predators (birds and lizards), the variability also occurs in similar regions of their VSDs. In accordance with the sequence logo, the insects have only one variable loop (Fig. 7B). These results suggest that the amino acid variability observed within the VSD in predators and prey of scorpions is a consequence of relaxed purifying selection, leading to their higher evolutionary rates.


Target-Driven Evolution of Scorpion Toxins.

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

Sequence logos.(A) Nav channel VSDs from birds, lizards, mammals and insects; (B) Scorpion α-toxins. Each logo consists of stacks of letters and the overall height of each stack indicates the sequence conservation at that position (measured in bits). The height of symbols within the stack reflects the relative frequency of the corresponding amino acid at that position39. Loops involved in toxin-channel interaction are boxed in orange in both toxins and channels; and positions of amino acids implicated in binding of rNav1.2 to Lqh225 are labeled by asterisks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Sequence logos.(A) Nav channel VSDs from birds, lizards, mammals and insects; (B) Scorpion α-toxins. Each logo consists of stacks of letters and the overall height of each stack indicates the sequence conservation at that position (measured in bits). The height of symbols within the stack reflects the relative frequency of the corresponding amino acid at that position39. Loops involved in toxin-channel interaction are boxed in orange in both toxins and channels; and positions of amino acids implicated in binding of rNav1.2 to Lqh225 are labeled by asterisks.
Mentions: Given the extensive existence of co-evolution between proteins and their interaction partners (e.g. ligand-receptor pairs)3738, the lack of matched PSSs in the toxin-bound region of Nav channels is puzzling as strong positive selection signals exist in the channel-bound region of the toxins (Fig. 3). To address this puzzling, we further analyzed sequence conservation in the VSD using WebLogo, a web-based application designed to make the generation of sequence logos39. The results indicate that the two loops (LDIVS1-S2; LDIVS3-S4) are highly variable in birds, lizards and mammals relative to their adjacent transmembrane helices (S1–S4) that show more conservation (Fig. 6A). In insects, more variability was also found in LDIVS1-S2. In parallel, we calculated the sequence logo of the toxin family, confirming the variability of the two positively selected loops (B- and J-loop) (Fig. 6B). The evolutionary variability of the toxin-bound region in VSDs of the Nav channels is further confirmed by ConSurf, an algorithmic tool for the identification of variable and conserved regions in proteins by surface mapping of phylogenetic information40. As shown in Fig. 7A, BmKM1 binds to the two variable loops of the mammalian VSDs primarily via its PSSs (shown in blue). In the other two vertebrate predators (birds and lizards), the variability also occurs in similar regions of their VSDs. In accordance with the sequence logo, the insects have only one variable loop (Fig. 7B). These results suggest that the amino acid variability observed within the VSD in predators and prey of scorpions is a consequence of relaxed purifying selection, leading to their higher evolutionary rates.

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.