The direction of protein evolution is destined by the stability

Biochimie
Natsuko OtaKazufumi Takano

Abstract

Protein evolution is potentially governed by protein stability. Here, we investigated the relationship between protein evolution and stability through the random mutational drift of a thermophilic bacterial protein, an esterase of Alicyclobacillus acidocaldarius (Aac-Est), at high and low temperatures. In the first random mutation of Aac-Est, few proteins exhibit increased activity at 65 °C, indicating that the wild-type (WT) Aac-Est is located on the peak of a mountain in a fitness landscape for activity at high temperature. To obtain higher active variants than those of WT, it must go down the mountain once and climb another, higher mountain. In the second and third generations from lower active templates, the evolvability (the proportion of variants with higher activity in all the variants obtained in a given generation than a parent protein) depended on the stability of the template proteins. Compared to WT, the stability-maintaining template could recover the activity more. Thus, a low-activity variant with high stability is able to drift vastly in sequence space and reach the foot of a higher mountain. Meanwhile, random mutations in stability-loss templates produced several variants with higher activity at 40 °C than thos...Continue Reading

Citations

Jan 3, 2019·Annual Review of Biophysics·Celia BlancoIrene A Chen
Feb 23, 2021·The Journal of Biological Chemistry·Peter G ChandlerAshley M Buckle

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