title: Cdc123, a Cell Cycle Regulator Needed for eIF2 Assembly, Is an ATP-Grasp Protein with Unique Features.
abstract: Eukaryotic initiation factor 2 (eIF2), a heterotrimeric guanosine triphosphatase, has a central role in protein biosynthesis by supplying methionylated initiator tRNA to the ribosomal translation initiation complex and by serving as a target for translational control in response to stress. Recent work identified a novel step indispensable for eIF2 function: assembly of eIF2 from its three subunits by the cell proliferation protein Cdc123. We report the first crystal structure of a Cdc123 representative, that from Schizosaccharomyces pombe, both isolated and bound to domain III of Saccharomyces cerevisiae eIF2γ. The structures show that Cdc123 resembles enzymes of the ATP-grasp family. Indeed, Cdc123 binds ATP-Mg(2+), and conserved residues contacting ATP-Mg(2+) are essential for Cdc123 to support eIF2 assembly and cell viability. A docking of eIF2αγ onto Cdc123, combined with genetic and biochemical experiments, allows us to propose a model explaining how Cdc123 participates in the biogenesis of eIF2 through facilitating assembly of eIF2γ to eIF2α.
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS, UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Panvert
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS, UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dubiez
authors.affiliation: Department of Genetics, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Arnold
authors.affiliation: SOLEIL Synchrotron, L'Orme des Merisiers, 91190 Saint Aubin, France.
authors.forename: Javier
authors.initials: J
authors.lastname: Perez
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS, UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mechulam
authors.affiliation: Department of Genetics, University of Regensburg, 93040 Regensburg, Germany. Electronic address: wolfgang.seufert@ur.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seufert
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS, UMR7654, 91128 Palaiseau Cedex, France. Electronic address: emma@bioc.polytechnique.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Schmitt
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D000255:Adenosine Triphosphate