Adaptive Mutations that Prevent Crosstalk Enable the Expansion of Paralogous Signaling Protein Families

• Published in: Cell 2012-07, Vol.150 (1), p.222-232
• Main Authors: Capra, Emily J., Perchuk, Barrett S., Skerker, Jeffrey M., Laub, Michael T.
• Format: Article
• Language: English
• Subjects: alpha-Proteobacteria; Alphaproteobacteria - genetics; Alphaproteobacteria - metabolism; Bacterial Proteins - genetics; divergent evolution; Evolution, Molecular; insulating materials; Mutation; Phylogeny; proteins; Selection, Genetic; Signal Transduction
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.05.033

Orthologous proteins often harbor numerous substitutions, but whether these differences result from neutral or adaptive processes is usually unclear. To tackle this challenge, we examined the divergent evolution of a model bacterial signaling pathway comprising the kinase PhoR and its cognate substrate PhoB. We show that the specificity-determining residues of these proteins are typically under purifying selection but have, in α-proteobacteria, undergone a burst of diversification followed by extended stasis. By reversing mutations that accumulated in an α-proteobacterial PhoR, we demonstrate that these substitutions were adaptive, enabling PhoR to avoid crosstalk with a paralogous pathway that arose specifically in α-proteobacteria. Our findings demonstrate that duplication and the subsequent need to avoid crosstalk strongly influence signaling protein evolution. These results provide a concrete example of how system-wide insulation can be achieved postduplication through a surprisingly limited number of mutations. Our work may help explain the apparent ease with which paralogous protein families expanded in all organisms. [Display omitted] ► The prevention of crosstalk constrains the evolution of signaling proteins ► Unless duplicated, the specificity residues of signaling proteins rarely change ► Avoiding crosstalk between pathways after duplication is a major selective pressure ► Insulating duplicated signaling proteins requires changes in specificity residues Following gene duplication, selective pressure to avoid signaling crosstalk drives gene divergence, promoting a burst of mutations in specificity determining residues.