8PHD

Structure of Human Cdc123 bound to domain 3 of eIF2 gamma and ATP

Summary for 8PHD

• Entry DOI: 10.2210/pdb8phd/pdb
• Descriptor: Cell division cycle protein 123 homolog, Eukaryotic translation initiation factor 2 subunit 3, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: eif2, translation initiation, chaperone, cdc123, atp grasp, translation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 108460.03

Authors

Schmitt, E.,Mechulam, Y.,Cardenal Peralta, C.,Fagart, J.,Seufert, W. (deposition date: 2023-06-19, release date: 2023-08-16, Last modification date: 2023-09-06)

Primary citation

Cardenal Peralta, C.,Vandroux, P.,Neumann-Arnold, L.,Panvert, M.,Fagart, J.,Seufert, W.,Mechulam, Y.,Schmitt, E.
Binding of human Cdc123 to eIF2 gamma.
J.Struct.Biol., 215:108006-108006, 2023

PubMed Abstract: Eukaryotic initiation factor 2 (eIF2) plays a key role in protein synthesis and in its regulation. The assembly of this heterotrimeric factor is facilitated by Cdc123, a member of the ATP grasp family that binds the γ subunit of eIF2. Notably, some mutations related to MEHMO syndrome, an X-linked intellectual disability, affect Cdc123-mediated eIF2 assembly. The mechanism of action of Cdc123 is unclear and structural information for the human protein is awaited. Here, the crystallographic structure of human Cdc123 (Hs-Cdc123) bound to domain 3 of human eIF2γ (Hs-eIF2γD3) was determined. The structure shows that the domain 3 of eIF2γ is bound to domain 1 of Cdc123. In addition, the long C-terminal region of Hs-Cdc123 provides a link between the ATP and Hs-eIF2γD3 binding sites. A thermal shift assay shows that ATP is tightly bound to Cdc123 whereas the affinity of ADP is much smaller. Yeast cell viability experiments, western blot analysis and two-hybrid assays show that ATP is important for the function of Hs-Cdc123 in eIF2 assembly. These data and recent findings allow us to propose a refined model to explain the mechanism of action of Cdc123 in eIF2 assembly.

PubMed: 37507029
DOI: 10.1016/j.jsb.2023.108006

Experimental method

X-RAY DIFFRACTION (2.08 Å)