Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence.

ABSTRACT: A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line wit

SUBMITTER: Mohammadi S 

PROVIDER: S-EPMC9462791 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature