title: Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation.
abstract: Trimeric G protein signaling is a fundamental mechanism of cellular communication in eukaryotes. The core of this mechanism consists of activation of G proteins by the guanine-nucleotide exchange factor (GEF) activity of G protein coupled receptors. However, the duration and amplitude of G protein-mediated signaling are controlled by a complex network of accessory proteins that appeared and diversified during evolution. Among them, nonreceptor proteins with GEF activity are the least characterized. We recently found that proteins of the ccdc88 family possess a Gα-binding and activating (GBA) motif that confers GEF activity and regulates mammalian cell behavior. A sequence similarity-based search revealed that ccdc88 genes are highly conserved across metazoa but the GBA motif is absent in most invertebrates. This prompted us to investigate whether the GBA motif is present in other nonreceptor proteins in invertebrates. An unbiased bioinformatics search in Caenorhabditis elegans identified GBAS-1 (GBA and SPK domain containing-1) as a GBA motif-containing protein with homologs only in closely related worm species. We demonstrate that GBAS-1 has GEF activity for the nematode G protein GOA-1 and that the two proteins are coexpressed in many cells of living worms. Furthermore, we show that GBAS-1 can activate mammalian Gα-subunits and provide structural insights into the evolutionarily conserved determinants of the GBA-G protein interface. These results demonstrate that the GBA motif is a functional GEF module conserved among highly divergent proteins across evolution, indicating that the GBA-Gα binding mode is strongly constrained under selective pressure to mediate receptor-independent G protein activation in metazoans.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Brantley D
authors.initials: BD
authors.lastname: Coleman
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Arthur
authors.initials: A
authors.lastname: Marivin
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Parag-Sharma
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Vincent
authors.initials: V
authors.lastname: DiGiacomo
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine.
authors.forename: Seongseop
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Pepper
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Jason
authors.initials: J
authors.lastname: Casler
authors.affiliation: Department of Biochemistry, Boston University School of Medicine.
authors.forename: Lien T
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Koelle
authors.affiliation: Department of Biochemistry, Boston University School of Medicine mgm1@bu.edu.
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D020662:Guanine Nucleotide Exchange Factors; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins
keywords: C. elegans; DAPLE; GOA-1; Girdin; Ric-8