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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.


High variability of scorpion α-toxin-bound regions in Nav channels from both predators and prey of scorpions.(A) Molecular surface display shows that BmKM1 binds to the evolutionarily variable loops (LDIVS1-S2 and LDIVS3-S4) of the VSD via its PSSs (blue). The complex model is the same with that of Fig. 3; (B) Molecular surfaces of VSDs from birds, lizards and insects. Variable regions involved in toxin binding are circled. Consurf (http://consurf.tau.ac.il/) was introduced to compute the position-specific conservation scores in the VSD and colored according to the scores. Structures of bird, lizard and insect VSDs are modeled from sequences of Picoides pubescens (gi/699624821), Anolis carolinensis (gi/343098400) and Drosophila melanogaster (gi/403447) (Figs. S2, S3 and S5) based on the previously reported rNav1.2 model29. Faces A and B are two faces of the VSD rotated 180° around y axis.
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f7: High variability of scorpion α-toxin-bound regions in Nav channels from both predators and prey of scorpions.(A) Molecular surface display shows that BmKM1 binds to the evolutionarily variable loops (LDIVS1-S2 and LDIVS3-S4) of the VSD via its PSSs (blue). The complex model is the same with that of Fig. 3; (B) Molecular surfaces of VSDs from birds, lizards and insects. Variable regions involved in toxin binding are circled. Consurf (http://consurf.tau.ac.il/) was introduced to compute the position-specific conservation scores in the VSD and colored according to the scores. Structures of bird, lizard and insect VSDs are modeled from sequences of Picoides pubescens (gi/699624821), Anolis carolinensis (gi/343098400) and Drosophila melanogaster (gi/403447) (Figs. S2, S3 and S5) based on the previously reported rNav1.2 model29. Faces A and B are two faces of the VSD rotated 180° around y axis.

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)

High variability of scorpion α-toxin-bound regions in Nav channels from both predators and prey of scorpions.(A) Molecular surface display shows that BmKM1 binds to the evolutionarily variable loops (LDIVS1-S2 and LDIVS3-S4) of the VSD via its PSSs (blue). The complex model is the same with that of Fig. 3; (B) Molecular surfaces of VSDs from birds, lizards and insects. Variable regions involved in toxin binding are circled. Consurf (http://consurf.tau.ac.il/) was introduced to compute the position-specific conservation scores in the VSD and colored according to the scores. Structures of bird, lizard and insect VSDs are modeled from sequences of Picoides pubescens (gi/699624821), Anolis carolinensis (gi/343098400) and Drosophila melanogaster (gi/403447) (Figs. S2, S3 and S5) based on the previously reported rNav1.2 model29. Faces A and B are two faces of the VSD rotated 180° around y axis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: High variability of scorpion α-toxin-bound regions in Nav channels from both predators and prey of scorpions.(A) Molecular surface display shows that BmKM1 binds to the evolutionarily variable loops (LDIVS1-S2 and LDIVS3-S4) of the VSD via its PSSs (blue). The complex model is the same with that of Fig. 3; (B) Molecular surfaces of VSDs from birds, lizards and insects. Variable regions involved in toxin binding are circled. Consurf (http://consurf.tau.ac.il/) was introduced to compute the position-specific conservation scores in the VSD and colored according to the scores. Structures of bird, lizard and insect VSDs are modeled from sequences of Picoides pubescens (gi/699624821), Anolis carolinensis (gi/343098400) and Drosophila melanogaster (gi/403447) (Figs. S2, S3 and S5) based on the previously reported rNav1.2 model29. Faces A and B are two faces of the VSD rotated 180° around y axis.
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.