ArticleMolecular biology and evolution2022
Epistatic Effects Between Amino Acid Insertions and Substitutions Mediate Toxin resistance of Vertebrate Na+,K+-ATPases.
Article in Molecular biology and evolution, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 9 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
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- From Trees to Traits: A Review of Advances in PhyloG2P Methods and Future Directions.Genome biology and evolution · 2025Review
- Substrate Specificity of ABCB Transporters Predicted by Docking Simulations Can Be Confirmed by Experimental Tests.Molecules (Basel, Switzerland) · 2024Article
- WGCCRR: a web-based tool for genome-wide screening of convergent indels and substitutions of amino acids.Bioinformatics advances · 2024Article
- Predatory fireflies and their toxic firefly prey have evolved distinct toxin resistance strategies.Current biology : CB · 2023Article
- Predatory fireflies and their toxic firefly prey have evolved distinct toxin resistance strategies.bioRxiv : the preprint server for biology · 2023Article
- Tissue-specific plant toxins and adaptation in a specialist root herbivore.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
- Retracted
Authors and funding
11 authors at 9 institutions in 7 countries.
Funding
Abstract
The recurrent evolution of resistance to cardiotonic steroids (CTS) across diverse animals most frequently involves convergent amino acid substitutions in the H1-H2 extracellular loop of Na+,K+-ATPase (NKA). Previous work revealed that hystricognath rodents (e.g., chinchilla) and pterocliform birds (sandgrouse) have convergently evolved amino acid insertions in the H1-H2 loop, but their functional significance was not known. Using protein engineering, we show that these insertions have distinct effects on CTS resistance in homologs of each of the two species that strongly depend on intramolecular interactions with other residues. Removing the insertion in the chinchilla NKA unexpectedly increases CTS resistance and decreases NKA activity. In the sandgrouse NKA, the amino acid insertion and substitution Q111R both contribute to an augmented CTS resistance without compromising ATPase activity levels. Molecular docking simulations provide additional insight into the biophysical mechanisms responsible for the context-specific mutational effects on CTS insensitivity of the enzyme. Our results highlight the diversity of genetic substrates that underlie CTS insensitivity in vertebrate NKA and reveal how amino acid insertions can alter the phenotypic effects of point mutations at key sites in the same protein domain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.