title: The domain architecture of large guanine nucleotide exchange factors for the small GTP-binding protein Arf.
abstract: BACKGROUND
  Small G proteins, which are essential regulators of multiple cellular functions, are activated by guanine nucleotide exchange factors (GEFs) that stimulate the exchange of the tightly bound GDP nucleotide by GTP. The catalytic domain responsible for nucleotide exchange is in general associated with non-catalytic domains that define the spatio-temporal conditions of activation. In the case of small G proteins of the Arf subfamily, which are major regulators of membrane trafficking, GEFs form a heterogeneous family whose only common characteristic is the well-characterized Sec7 catalytic domain. In contrast, the function of non-catalytic domains and how they regulate/cooperate with the catalytic domain is essentially unknown.
  
  
  RESULTS
  Based on Sec7-containing sequences from fully-annotated eukaryotic genomes, including our annotation of these sequences from Paramecium, we have investigated the domain architecture of large ArfGEFs of the BIG and GBF subfamilies, which are involved in Golgi traffic. Multiple sequence alignments combined with the analysis of predicted secondary structures, non-structured regions and splicing patterns, identifies five novel non-catalytic structural domains which are common to both subfamilies, revealing that they share a conserved modular organization. We also report a novel ArfGEF subfamily with a domain organization so far unique to alveolates, which we name TBS (TBC-Sec7).
  
  
  CONCLUSIONS
  Our analysis unifies the BIG and GBF subfamilies into a higher order subfamily, which, together with their being the only subfamilies common to all eukaryotes, suggests that they descend from a common ancestor from which species-specific ArfGEFs have subsequently evolved. Our identification of a conserved modular architecture provides a background for future functional investigation of non-catalytic domains.
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, avenue de la Terrasse, 91198 Gif sur Yvette cedex, France. mouratou@lebs.cnrs-gif.fr
authors.forename: Barbara
authors.initials: B
authors.lastname: Mouratou
authors.forename: Valerie
authors.initials: V
authors.lastname: Biou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Joubert
authors.forename: Jean
authors.initials: J
authors.lastname: Cohen
authors.forename: David J
authors.initials: DJ
authors.lastname: Shields
authors.forename: Niko
authors.initials: N
authors.lastname: Geldner
authors.forename: Gerd
authors.initials: G
authors.lastname: Jürgens
authors.forename: Paul
authors.initials: P
authors.lastname: Melançon
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cherfils
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry*; D000465:Algorithms; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D016785:Cryptosporidium parvum / Q000378:metabolism; D030541:Databases, Genetic; D019143:Evolution, Molecular; D019204:GTP-Binding Proteins / Q000737:chemistry*; D016678:Genome; D006056:Golgi Apparatus / Q000378:metabolism; D006147:Guanine / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010247:Paramecium / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D017386:Sequence Homology, Amino Acid; D012984:Software; D016808:Tetrahymena thermophila / Q000378:metabolism; D013997:Time Factors
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C066755:Sec7 guanine nucleotide exchange factors; D006147:Guanine; D019204:GTP-Binding Proteins; D020727:ADP-Ribosylation Factors
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