Evolution of a signaling nexus constrained by protein interfaces and conformational States.

ABSTRACT: Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The G? subunit of the G protein, in particular, is highly constrained due to its many interactions with proteins that control or react to its conformational state. Various organisms contain differing sets of G?-interacting proteins, clearly indicating that shifts in sequence and associated G? functionality were acquired over time. These numerous interactions constrained much of G? evolution; yet G? has diversified, through poorly understood processes, into several functionally specialized classes, each with a unique set of interacting proteins. Applying a synthetic sequence-based approach to mammalian G? subunits, we established a set of seventy-five evolutionarily important class-distinctive residues, sites where a single G? class is differentiated from the three other classes. We tested the hypothesis that shifts at these sites are important for class-specific functionality. Importantly, we mapped known and well-studied class-specific functionalities from all four mammalian classes to sixteen of our class-distinctive sites, validating the hypothesis. Our results show how unique functionality can evolve through the recruitment of residues that were ancestrally functional. We also studied acquisition of functionalities by following these evolutionarily important sites in non-mammalian organisms. Our results suggest that many class-distinctive sites were established early on in eukaryotic diversification and were critical for the establishment of new G? classes, whereas others arose in punctuated bursts throughout metazoan evolution. These G? class-distinctive residues are rational targets for future structural and functional studies.

SUBMITTER: Temple BR 

PROVIDER: S-EPMC2954821 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature