ArticleProceedings of the National Academy of Sciences of the United States of America2019
Comparing mutagenesis and simulations as tools for identifying functionally important sequence changes for protein thermal adaptation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 65 citations in OpenAlex.
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- RNA editing generates mRNA isoforms with distinct stabilities that may expand the thermal tolerance of mRNA and proteins inZoological research · 2025Article
- Thermal Adaptation of Cytosolic Malate Dehydrogenase Revealed by Deep Learning and Coevolutionary Analysis.Journal of chemical theory and computation · 2025Article
- Phylogenetic history and temperature adaptation contribute to structural and functional stability of proteins in marine mollusks.Communications biology · 2025Article
- The structural insights of L-asparaginase from3 Biotech · 2024Article
- Proanthocyanidin B2 derived metabolites may be ligands for bile acid receptors S1PR2, PXR and CAR: anJournal of biomolecular structure & dynamics · 2024Article
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- Predicting thermostability difference between cellular protein orthologs.Bioinformatics (Oxford, England) · 2023Article
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- Principles of Cold Adaptation of Fish Lactate Dehydrogenases Revealed by Computer Simulations of the Catalytic Reaction.Molecular biology and evolution · 2023Article
- Data-driven strategies for the computational design of enzyme thermal stability: trends, perspectives, and prospects.Acta biochimica et biophysica Sinica · 2023Review
- Solutions: how adaptive changes in cellular fluids enable marine life to cope with abiotic stressors.Marine life science & technology · 2022Review
- Thermal adaptation of mRNA secondary structure: stability versus lability.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Bioinformatic analysis of subfamily-specific regions in 3D-structures of homologs to study functional diversity and conformational plasticity in protein superfamilies.Computational and structural biotechnology journal · 2021Article
- Acetylome Analysis Reveals Population Differentiation of the Pacific Oyster Crassostrea gigas in Response to Heat Stress.Marine biotechnology (New York, N.Y.) · 2020Article
- Early Stage Adaptation of a Mesophilic Green Alga to Antarctica: Systematic Increases in Abundance of Enzymes and LEA Proteins.Molecular biology and evolution · 2020Article
- High-throughput quantification of protein structural change reveals potential mechanisms of temperature adaptation in Mytilus mussels.BMC evolutionary biology · 2020Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Comparative studies of orthologous proteins of species evolved at different temperatures have revealed consistent patterns of temperature-related variation in thermal stabilities of structure and function. However, the precise mechanisms by which interspecific variations in sequence foster these adaptive changes remain largely unknown. Here, we compare orthologs of cytosolic malate dehydrogenase (cMDH) from marine molluscs adapted to temperatures ranging from -1.9 °C (Antarctica) to ∼55 °C (South China coast) and show how amino acid usage in different regions of the enzyme (surface, intermediate depth, and protein core) varies with adaptation temperature. This eukaryotic enzyme follows some but not all of the rules established in comparisons of archaeal and bacterial proteins. To link the effects of specific amino acid substitutions with adaptive variations in enzyme thermal stability, we combined site-directed mutagenesis (SDM) and in vitro protein experimentation with in silico mutagenesis using molecular dynamics simulation (MDS) techniques. SDM and MDS methods generally but not invariably yielded common effects on protein stability. MDS analysis is shown to provide insights into how specific amino acid substitutions affect the conformational flexibilities of mobile regions (MRs) of the enzyme that are essential for binding and catalysis. Whereas these substitutions invariably lie outside of the MRs, they effectively transmit their flexibility-modulating effects to the MRs through linked interactions among surface residues. This discovery illustrates that regions of the protein surface lying outside of the site of catalysis can help establish an enzyme's thermal responses and foster evolutionary adaptation of function.
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