@article {Lachowiec006411, author = {Jennifer Lachowiec and Tzitziki Lemus and Elhanan Borenstein and Christine Queitsch}, title = {Hsp90 promotes kinase evolution}, elocation-id = {006411}, year = {2014}, doi = {10.1101/006411}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Heat-shock protein 90 (Hsp90) promotes the maturation and stability of its client proteins, including many kinases. In doing so, Hsp90 may allow its clients to accumulate mutations as previously proposed by the capacitor hypothesis. If true, Hsp90 clients should show increased evolutionary rate compared to non-clients; however, other factors, such as gene expression and protein connectivity, may confound or obscure the chaperone{\textquoteright}s putative contribution. Here, we compared the evolutionary rates of many Hsp90 clients and non-clients in the human protein kinase superfamily. We show that Hsp90 client status promotes evolutionary rate independently of, but in a similar magnitude to, gene expression and protein connectivity. Hsp90{\textquoteright}s effect on kinase evolutionary rate was detected across mammals and increased with time of divergence. Hsp90 clients also showed increased nucleotide diversity and harbored more damaging variation than non-client kinases across humans. These results are consistent with the central argument of the capacitor hypothesis that interaction with the chaperone allows its clients to harbor genetic variation. Hsp90 client status is thought to be highly dynamic with as few as one amino acid change rendering a protein dependent on the chaperone. Contrary to this expectation, we found that across protein kinase phylogeny Hsp90 client status tends to be gained, maintained, and shared among closely related kinases. We also infer that the ancestral protein kinase was not an Hsp90 client. Taken together, our results suggest that Hsp90 played an important role in shaping the kinase superfamily.}, URL = {https://www.biorxiv.org/content/early/2014/06/19/006411}, eprint = {https://www.biorxiv.org/content/early/2014/06/19/006411.full.pdf}, journal = {bioRxiv} }