Scorpion Toxins: Positive Selection at a Distal Site Modulates Functional Evolution at a Bioactive Site

Abstract

The bioactive sites of proteins are those that directly interact with their targets. In many immunity- and predation-related proteins, they frequently experience positive selection for dealing with the changes of their targets from competitors. However, some sites that are far away from the interface between proteins and their targets are also identified to evolve under positive selection. Here, we explore the evolutionary implication of such a site in scorpion α-type toxins affecting sodium (Na+) channels (abbreviated as α-ScNaTxs) using a combination of experimental and computational approaches. We found that despite no direct involvement in interaction with Na+ channels, mutations at this site by different types of amino acids led to toxicity change on both rats and insects in three α-ScNaTxs, accompanying differential effects on their structures. Molecular dynamics simulations indicated that the mutations changed the conformational dynamics of the positively selected bioactive site-containing functional regions by allosteric communication, suggesting a potential evolutionary correlation between these bioactive sites and the distant nonbioactive site. Our results reveal for the first time the cause of fast evolution at nonbioactive sites of scorpion neurotoxins, which is presumably to adapt to the change of their bioactive sites through coevolution to maintain an active conformation for channel binding. This might aid rational design of scorpion Na+ channel toxins with improved phyletic selectivity via modification of a distant nonbioactive site.

Parasitoid Serpins Evolve Novel Functions to Manipulate Host Homeostasis

“…Positive selection of specific functional sites in gene functional regions is an indispensable driving force to shape novel niches following gene duplication ( Thomas et al 2005 ; Qian et al 2017 ; Zhu et al 2019 ; Yang et al 2020 ; Jovanovic et al 2021 ). The RCL of serpins extends outwards from the protein surface and acts as a decoy for its homologous proteases, determining serpin activity and specificity ( Meekins et al 2017 ).…”

Rational optimization of a human neutralizing antibody of SARS-CoV-2

“…Most of the predictions made by our approach are consistent with mmCSM-AB [ 59 ], a recently developed benchmarked method using graph-based signatures and atomic interaction information in analyzing mutations on antigen binding affinity, confirming that our methodology is of reliability ( Supplementary Table S3 ). Unlike previous studies that rely on researchers’ expertise to select possible mutations [ [60] , [61] , [62] ], this workflow can be easily performed on high-performance clusters or supercomputers without such expertise. Moreover, our designed workflow can also be applied to optimizing other protein drugs.…”