title: Structural mimicry of DH domains by Arfaptin suggests a model for the recognition of Rac-GDP by its guanine nucleotide exchange factors.
abstract: Small G proteins cycle between an inactive form bound to GDP, and an active form bound to GTP. The two forms have different conformations and interact specifically with different partners, hence, the ability of G proteins to function as molecular switches. This view has been challenged by recent structural and biochemical studies of the Arfaptin/Por protein, which interacts equally well with the GDP- and GTP-bound forms of the G protein Rac. Here it is shown that the dimeric helical domain of Arfaptin superimposes with a monomeric helical domain from the Dbl homology domain of Tiam, a guanine nucleotide exchange factor (GEF) for Rac, in their respective complexes with Rac. This unexpected structural mimicry suggests that the Rac-GDP-Arfaptin complex resembles the low-affinity Rac-GDP-GEF complex that initiates the exchange reaction. This provides a model for the exchange mechanism where DH domains first dock onto Rac-GDP at the switch 2 before they undergo domain closure to catalyze GDP dissociation.
authors.affiliation: Laboratoire d'Enzymologie et Biochimie Structurales, UPR 9063 CNRS, 1 avenue de la Terrasse, 91198 Cedex, Gif sur Yvette, France. cherfils@lebs-cnrs-gif.fr
authors.forename: J
authors.initials: J
authors.lastname: Cherfils
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D006153:Guanosine Diphosphate / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C105088:ARFIP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D011506:Proteins; D006153:Guanosine Diphosphate; D020744:rac GTP-Binding Proteins