Protein structure is a major determinant of protein evolution at the residue level. It is especially challenging to elucidate the relationship between structure and evolution for proteins that adopt several different conformations due to their function. Previously, we showed that proteins that switch between different native states are on average under stronger selective pressure than proteins with a single native state. Here, we analyzed evolutionary rates at the residue level for proteins that switch between disordered and ordered states in the yeast proteome. We show that while proteins with completely disordered regions generally evolve more rapidly than structured proteins, proteins with disorder-order switching regions evolve significantly more slowly on average. Surprisingly, proteins with disorder-order switching regions on average evolve even more slowly than conformational switches, which are known to be highly conserved. The elevated selective pressure on proteins with disorder-order switching regions is exerted on the entire protein, such that even the ordered residues in these proteins are on average more conserved than the ordered residues in structured proteins. While disordered residues generally evolve more rapidly than ordered residues within a protein, disordered regions that can switch into ordered states are highly conserved compared with other disordered residues. Overall, our results suggest that the necessity to encode and maintain coupled folding and binding imposes a unique and strong selective pressure on the entire protein.

• PMID: 40549344
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Journal Article

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Sharir-Ivry A, Xia Y

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