title: Eukaryotic G protein signaling evolved to require G protein-coupled receptors for activation.
abstract: Although bioinformatic analysis of the increasing numbers of diverse genome sequences and amount of functional data has provided insight into the evolution of signaling networks, bioinformatics approaches have limited application for understanding the evolution of highly divergent protein families. We used biochemical analyses to determine the in vitro properties of selected divergent components of the heterotrimeric guanine nucleotide-binding protein (G protein) signaling network to investigate signaling network evolution. In animals, G proteins are activated by cell-surface seven-transmembrane (7TM) receptors, which are named G protein-coupled receptors (GPCRs) and function as guanine nucleotide exchange factors (GEFs). In contrast, the plant G protein is intrinsically active, and a 7TM protein terminates G protein activity by functioning as a guanosine triphosphatase-activating protein (GAP). We showed that ancient regulation of the G protein active state is GPCR-independent and "self-activating," a property that is maintained in Bikonts, one of the two fundamental evolutionary clades containing eukaryotes, whereas G proteins of the other clade, the Unikonts, evolved from being GEF-independent to being GEF-dependent. Self-activating G proteins near the base of the Eukaryota are controlled by 7TM-GAPs, suggesting that the ancestral regulator of G protein activation was a GAP-functioning receptor, not a GEF-functioning GPCR. Our findings indicate that the GPCR paradigm describes a recently evolved network architecture found in a relatively small group of Eukaryota and suggest that the evolution of signaling network architecture is constrained by the availability of molecules that control the activation state of nexus proteins.
authors.affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: William
authors.initials: W
authors.lastname: Bradford
authors.forename: Adam
authors.initials: A
authors.lastname: Buckholz
authors.forename: John
authors.initials: J
authors.lastname: Morton
authors.forename: Collin
authors.initials: C
authors.lastname: Price
authors.forename: Alan M
authors.initials: AM
authors.lastname: Jones
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urano
mesh_terms: D019204:GTP-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006868:Hydrolysis; D009711:Nucleotides / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D014246:Trichomonas vaginalis / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009711:Nucleotides; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins