The adaptive potential of the M-domain of yeast Hsp90 [preprint]

Abstract

Comparing the distribution of fitness effects (DFE) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in other environments. So far, results regarding the cost of adaptation across environments have been mixed, and there were no sufficiently large data sets to map its variation along the genome. Here, we study the DFEs of ≈2500 amino-acid changing mutations obtained from deep mutational scanning of the 118 amino-acid-long middle domain of the heat-shock protein Hsp90 in five environments and at two expression levels. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-M and M-C interdomains and regulation of ATPase-chaperone activity. Despite the diverse and stressful environments, we find that fitness correlates well across environments, with the exception of one environment, diamide. Consistent with these results, we find very little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client binding interfaces or residues that are involved in ATPase chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information.