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Pervasive Divergence in Protein Thermostability is Mediated by Both Structural Changes and Cellular Environments

Nilima Walunjkar,Timothy Y. Lai,Nasima Akhter,James H. Miller,John Q. Bettinger,Erin Marcus,E. Phizicky,Sina Ghaemmaghami,Justin C. Fay

Published 2025 in Molecular biology and evolution

ABSTRACT

Abstract Temperature is a universal environmental constraint and organisms have evolved diverse mechanisms of thermotolerance. A central feature of thermophiles relative to mesophiles is a universal shift in protein stability, implying that it is a major constituent of thermotolerance. However, organisms have also evolved extensive buffering systems, such as those that disaggregate and refold denatured proteins and enable survival of heat shock. Here, we show that both cellular and protein structural changes contribute to divergence in protein thermostability between two closely related Saccharomyces species that differ by 8 °C in their thermotolerance. Using thermal proteomic profiling we find that 85% of S. cerevisiae proteins are more stable than their S. uvarum homologs and there is a 1.6 °C shift in average protein melting temperature. In an interspecific hybrid of the two species, S. cerevisiae proteins retain their thermostability, while the thermostability of their S. uvarum homologs is enhanced, indicating that cellular context contributes to protein stability differences. By purifying orthologous proteins, we show that amino acid substitutions underlie melting temperature differences for two proteins, Guk1 and Aha1. Amino acid substitutions are also computationally predicted to contribute to stability differences for most of the proteome. Our results imply that widespread changes in protein thermostability accompany the evolution of thermotolerance between closely related species.

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