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.

GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes

“…[32][33][34][35] For example, ATP is required for the release of the anaphase-promoting complex / cyclosome from inhibition by the mitotic checkpoint. 33 Cdc123, another cell cycle regulator, is identified as an ATP-Grasp protein that functions in cell cycle regulation by catalyzing protein modifications in an ATP-dependent manner.…”

“…33 Cdc123, another cell cycle regulator, is identified as an ATP-Grasp protein that functions in cell cycle regulation by catalyzing protein modifications in an ATP-dependent manner. 34 In mouse oocytes, the decrease in mitochondrially derived ATP may induce disassembly of MII oocyte spindles. 35 Per our cytologic analysis, Elmod2 knockdown caused a series of meiotic problems, including a delay in progression to meiosis I and II.…”

Stepwise assembly of the eukaryotic translation initiation factor 2 complex

“…This was also thought to indicate a dependency of eIF2β binding on prior binding of eIF2α. In a crystallographic study, the interaction between eIF2γ and Cdc123 was resolved at the atomic level, which also revealed Cdc123's membership in the family of ATP grasp proteins (19). Members of this family of enzymes ligate carboxylic acids to nucleophilic groups; examples are biotin carboxylases, dipeptide synthetases and tubulin tyrosine ligase (20).…”

Clandestinovirus: A Giant Virus With Chromatin Proteins and a Potential to Manipulate the Cell Cycle of Its Host Vermamoeba vermiformis

“…Remarkably, clandestinovirus encodes two homologs of Cyclin A2 ( Cheng et al, 2006 ; Zhang et al, 2019 ), a factor that regulates cell cycle progression by interacting with two different cyclin-dependent kinases (CDK): CDK2 during S phase and CDK1 during the transition from G2 to M phase ( Pagano et al, 1992 ). In addition, clandestinovirus encodes a homolog of Cdc123, an ATP-grasp fold protein involved in cell cycle control by promoting the transition from G1 to S phase ( Panvert et al, 2015 ). Thus, clandestinovirus potentially orchestrate the cell cycle through controlling the phosphorylation state of key cellular factors as well as by direct interaction with the cellular or viral factors.…”