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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.


Detailed structural analysis of top 1 model of the ZDOCK complexes.(A) Ribbon models showing interactions between PSSs of toxins and residues derived from the VSD of rNav1.2, previously identified as a primary component of the receptor site for α-toxins (spheres in blue, PSSs and red, channel residues). Predicted contact residues between the toxin and the channel are indicated by arrows and dotted arrows illustrate residues forming salt bridges; (B). Molecular surface of BmKM1 and the VSD of rNav1.2 showing their interface (cycled), in which a ribbon structure of the backbone with side-chain atoms (space-filled) of PSSs and the channel residues is covered by a semi-transparent surface of the complex. The orientation of the ribbon structure is the same with that of Fig. 3A.
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f3: Detailed structural analysis of top 1 model of the ZDOCK complexes.(A) Ribbon models showing interactions between PSSs of toxins and residues derived from the VSD of rNav1.2, previously identified as a primary component of the receptor site for α-toxins (spheres in blue, PSSs and red, channel residues). Predicted contact residues between the toxin and the channel are indicated by arrows and dotted arrows illustrate residues forming salt bridges; (B). Molecular surface of BmKM1 and the VSD of rNav1.2 showing their interface (cycled), in which a ribbon structure of the backbone with side-chain atoms (space-filled) of PSSs and the channel residues is covered by a semi-transparent surface of the complex. The orientation of the ribbon structure is the same with that of Fig. 3A.

Mentions: In the complex structure, four toxin-VSD residues pairs were identified to contact directly, including: 1) Glu15/Ala17-L1611; 2) Arg18-Glu1613; 3) Trp38-Thr1560; and 4) Lys62-D1554, where pairs 2 and 4 form salt bridges to stabilize the complex structure (Fig. 3A). Evidences supporting the reliability of this complex come from the following observations: 1) Functional importance of the toxin residues (i.e. sites 15, 17, 18, 38 and 62) in the interface of the complex has been verified by prior mutagenesis data in multiple toxins, such as BmKM1, Lqh2, Lqh3 and LqhαIT19202122232430; 2) Thr1560 and Glu1613 have been found to be key residues of rNav1.2 implicated in Lqh2 binding and Glu1613 was previously identified as a primary component of the receptor site for α-toxins242531; 3) Pairs 1, 2 and 4 were also observed in the AaHII-rNav1.2 VSD model that was built based on atomistic molecular dynamics simulations29; 4) The overall orientation of the toxin relative to the VSD in our complex is similar to models of Lqh2-rNav1.225 and AaHII-rNav1.2. In these three complexes, residues from the toxin’s J-loop are close to LDIVS3-S4 of the channel and residues from the toxin’s B loop to LDIVS1-S2 (Fig. 3A). Apart from the four residues mentioned above implicated in direct contact with the channel, two additional PSSs (Q37 and V39) are also located on the interface of the complex (Fig. 3B). Only one exception in our complex is F1610, a channel residue derived from LDIVS3-S4 of rNav1.2 conferring to toxin binding25, is a bit far away from the interface (Fig. 3B). A possible explanation is that this residue directly interacts with the toxin through a conformational adjustment, as proposed in the Lqh2-rNav1.2 model25. Alternatively, this residue might have a synergistic role with its adjacent residue (e.g. L1611) to bind to the toxin (Fig. 3B).


Target-Driven Evolution of Scorpion Toxins.

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

Detailed structural analysis of top 1 model of the ZDOCK complexes.(A) Ribbon models showing interactions between PSSs of toxins and residues derived from the VSD of rNav1.2, previously identified as a primary component of the receptor site for α-toxins (spheres in blue, PSSs and red, channel residues). Predicted contact residues between the toxin and the channel are indicated by arrows and dotted arrows illustrate residues forming salt bridges; (B). Molecular surface of BmKM1 and the VSD of rNav1.2 showing their interface (cycled), in which a ribbon structure of the backbone with side-chain atoms (space-filled) of PSSs and the channel residues is covered by a semi-transparent surface of the complex. The orientation of the ribbon structure is the same with that of Fig. 3A.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Detailed structural analysis of top 1 model of the ZDOCK complexes.(A) Ribbon models showing interactions between PSSs of toxins and residues derived from the VSD of rNav1.2, previously identified as a primary component of the receptor site for α-toxins (spheres in blue, PSSs and red, channel residues). Predicted contact residues between the toxin and the channel are indicated by arrows and dotted arrows illustrate residues forming salt bridges; (B). Molecular surface of BmKM1 and the VSD of rNav1.2 showing their interface (cycled), in which a ribbon structure of the backbone with side-chain atoms (space-filled) of PSSs and the channel residues is covered by a semi-transparent surface of the complex. The orientation of the ribbon structure is the same with that of Fig. 3A.
Mentions: In the complex structure, four toxin-VSD residues pairs were identified to contact directly, including: 1) Glu15/Ala17-L1611; 2) Arg18-Glu1613; 3) Trp38-Thr1560; and 4) Lys62-D1554, where pairs 2 and 4 form salt bridges to stabilize the complex structure (Fig. 3A). Evidences supporting the reliability of this complex come from the following observations: 1) Functional importance of the toxin residues (i.e. sites 15, 17, 18, 38 and 62) in the interface of the complex has been verified by prior mutagenesis data in multiple toxins, such as BmKM1, Lqh2, Lqh3 and LqhαIT19202122232430; 2) Thr1560 and Glu1613 have been found to be key residues of rNav1.2 implicated in Lqh2 binding and Glu1613 was previously identified as a primary component of the receptor site for α-toxins242531; 3) Pairs 1, 2 and 4 were also observed in the AaHII-rNav1.2 VSD model that was built based on atomistic molecular dynamics simulations29; 4) The overall orientation of the toxin relative to the VSD in our complex is similar to models of Lqh2-rNav1.225 and AaHII-rNav1.2. In these three complexes, residues from the toxin’s J-loop are close to LDIVS3-S4 of the channel and residues from the toxin’s B loop to LDIVS1-S2 (Fig. 3A). Apart from the four residues mentioned above implicated in direct contact with the channel, two additional PSSs (Q37 and V39) are also located on the interface of the complex (Fig. 3B). Only one exception in our complex is F1610, a channel residue derived from LDIVS3-S4 of rNav1.2 conferring to toxin binding25, is a bit far away from the interface (Fig. 3B). A possible explanation is that this residue directly interacts with the toxin through a conformational adjustment, as proposed in the Lqh2-rNav1.2 model25. Alternatively, this residue might have a synergistic role with its adjacent residue (e.g. L1611) to bind to the toxin (Fig. 3B).

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.