Convergent Evolution of Novel Protein Function in Shrew and Lizard Venom

Abstract

How do proteins evolve novel functions? To address this question, we are studying the evolution of a mammalian toxin, the serine protease BLTX [1], from the salivary glands of the North American shrew Blarina brevicauda. Here, we examine the molecular changes responsible for promoting BLTX toxicity. First, we show that regulatory loops surrounding the BLTX active site have evolved adaptively via acquisition of small insertions and subsequent accelerated sequence evolution. Second, these mutations introduce a novel chemical environment into the catalytic cleft of BLTX. Third, molecular-dynamic simulations show that the observed changes create a novel chemical and physical topology consistent with increased enzyme catalysis. Finally, we show that a toxic serine protease from the Mexican beaded lizard (GTX) [2] has evolved convergently through almost identical functional changes. Together, these results suggest that the evolution of toxicity might be predictable-arising via adaptive structural modification of analogous labile regulatory loops of an ancestral serine protease-and thus might aid in the identification of other toxic proteins.

Parallel signatures of sequence evolution among hearing genes in echolocating mammals: an emerging model of genetic convergence

“…More extensive sequence convergence operating across several loci has been documented in the mitochondrial genomes of snakes and agamid lizards; however, mtDNA genes cannot be considered to represent independent loci, and the suggested potential adaptive role of such convergence in metabolism remains speculation (Castoe et al, 2009). Several different toxin protein genes have also been shown to have undergone convergent evolution, among different frog species (Roelants et al, 2010), as well as between shrews and lizards (Aminetzach et al, 2009), although the latter is structural as opposed to sequence convergence. In general, surprisingly few studies that have described sequence convergence have also tested for selection and, therefore, have not explicitly been able to rule out nonadaptive homoplasy that is widespread in nature (Rokas and Carroll, 2008).…”

Evolutionary Diversification of Mesobuthus α-Scorpion Toxins Affecting Sodium Channels

“…Given the J-loop carries crucial functional residues in several ␣-toxins (e.g. Lqh␣IT and Lqh2) (36,37), it is assumed that these changes in size could be associated with the divergence of MeuNaTx␣s, if any, by introducing a novel chemical environment (hydrophilic) into this binding loop of ␣-toxins, as previously observed in convergent evolution of novel function in serine proteases of shrew and lizard venom (38).…”

“…The LRT statistics (2⌬l) are 34.1 for M1a/M2a and 39.5 for M7/M8, which both are much greater than the 2 distribution critical values (p Ͻ 0.001), indicating the existence of positive selection in Mesobuthus ␣-toxins. Furthermore, M2a and M8 both convergently detected nine identical PSSs (8,9,15,18,20,38,39,41, and 50) ( Fig. 1; Table IV), of which sites 8 and 9 are located on the aminoterminal five-residue-turn; sites 15 and 18 preceding the ␣-helix; site 20 on the ␣-helix; sites 38 and 39 on the end of the second ␤-strand; site 41 on the ␤-turn linking the second and third ␤-strands; site 50 on the end of the last ␤-strand.…”

Functional and Structural Diversification of the Anguimorpha Lizard Venom System

“…The impact of this is not limited to interpretations of lizard venom molecular evolution but also decimates the central conclusion of a study that examined convergent mutation in kallikrein toxins between helodermatid lizards and shrews and in particular relied upon the questionable insert at alignment position 126 -132 as a key element (35). Toxin Structure-Function Relationships-Our functional testing of cholecystoxin, celestoxin, goannatyrotoxin, helokinestatin, and natriuretic peptide analogs demonstrated that all these peptide toxins target the vascular smooth muscle.…”