Evolution of a signaling nexus constrained by protein interfaces and conformational States.
Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The Gα 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 Gα-interacting proteins, clearly indicating that shifts in sequence and associated Gα functionality were acquired over time. These numerous interactions constrained much of Gα evolution; yet Gα 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 Gα subunits, we established a set of seventy-five evolutionarily important class-distinctive residues, sites where a single Gα 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 Gα classes, whereas others arose in punctuated bursts throughout metazoan evolution. These Gα class-distinctive residues are rational targets for future structural and functional studies.
R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. btemple@med.unc.edu
Brenda R S
BR
Temple
Corbin D
CD
Jones
Alan M
AM
Jones
D000262:Adenylyl Cyclases; D000595:Amino Acid Sequence; D000818:Animals; D030562:Databases, Protein; D056890:Eukaryota / Q000235:genetics; D019143:Evolution, Molecular; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry / Q000235:genetics; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007257:Information Theory; D008957:Models, Genetic; D008958:Models, Molecular; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D010802:Phylogeny; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics*
D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D000262:Adenylyl Cyclases