Structural basis for inhibition of translation by the tumor suppressor Pdcd4.
The tumor suppressor function of Programmed Cell Death 4 (Pdcd4) is achieved through interactions between Pdcd4 and components of the translation initiation complex, namely, the RNA helicase eIF4A and the scaffolding protein eIF4G. These interactions are mediated through two MA3 domains on the Pdcd4 molecule and result in inhibition of protein synthesis. We have solved the high-resolution crystal structure of the C-terminal MA3 (cMA3) domain of Pdcd4 in several crystal forms and demonstrated its similarity to the MA3 domain of eIF4G. As predicted by the structure, the cMA3 domain competes with eIF4Gc for binding to eIF4A and surprisingly is sufficient to inhibit translation initiation. Mutations that abolish eIF4A binding negate both functions of the cMA3. Interestingly mutations in the Akt phosphorylation site influenced neither cMA3 binding to eIF4A nor its ability to inhibit translation initiation. Finally, our structural analysis reveals MA3 domains to be a novel subfamily of VHS domains.
LaRonde-LeBlanc
Nicole
N
Macromolecular Crystallography Laboratory, CCR, National Cancer Institute, Frederick, MD 21702, USA. nlaronde@umd.edu
Santhanam
Arti N
AN
Baker
Alyson R
AR
Wlodawer
Alexander
A
Colburn
Nancy H
NH
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000502:physiology*; D039601:Eukaryotic Initiation Factor-4A / Q000502:physiology; D039603:Eukaryotic Initiation Factor-4G / Q000502:physiology; D005786:Gene Expression Regulation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques
D051017:Apoptosis Regulatory Proteins; D039603:Eukaryotic Initiation Factor-4G; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D039601:Eukaryotic Initiation Factor-4A