4axg
Structure of eIF4E-Cup complexStructure of eIF4E-Cup complex
Structural highlights
Function[IF4E_DROME] Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures.[1] [CUP_DROME] Adapter protein that plays a central role in localization of transcripts in the oocyte and in young embryos (PubMed:9118812). Maintains RNA targets in a repressed state by promoting their deadenylation and protects deadenylated mRNAs from further degradation (PubMed:21937713). Binds to and recruits eIF-4E to the 3'-UTR of some mRNA targets which prevents interaction between eIF-4E and eIF4G (PubMed:14685270, PubMed:15465908, PubMed:21081899). This may contribute to translational repression but does not appear to be necessary for it to occur. Can promote translational repression independently of deadenylation and eIF-4E binding (PubMed:21937713). Required for correct localization of eIF-4E in the developing oocyte (PubMed:15465908). Required for translational repression of oskar (osk) mRNA (PubMed:14691132, PubMed:14723848). Also required for the translational repression of nanos (nos) mRNA (PubMed:21081899). Promotes the accumulation of the germ plasm components osk, vas and stau at the posterior pole of the oocyte and is required for germ cell development (PubMed:22454519). Represses orb positive autoregulatory activity which prevents premature activation of orb and ensures its accumulation specifically in the developing oocyte (PubMed:22164257).[2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedCup is an eIF4E-binding protein (4E-BP) that plays a central role in translational regulation of localized mRNAs during early Drosophila development. In particular, Cup is required for repressing translation of the maternally contributed oskar, nanos, and gurken mRNAs, all of which are essential for embryonic body axis determination. Here, we present the 2.8 A resolution crystal structure of a minimal eIF4E-Cup assembly, consisting of the interacting regions of the two proteins. In the structure, two separate segments of Cup contact two orthogonal faces of eIF4E. The eIF4E-binding consensus motif of Cup (YXXXXLPhi) binds the convex side of eIF4E similarly to the consensus of other eIF4E-binding proteins, such as 4E-BPs and eIF4G. The second, noncanonical, eIF4E-binding site of Cup binds laterally and perpendicularly to the eIF4E beta-sheet. Mutations of Cup at this binding site were shown to reduce binding to eIF4E and to promote the destabilization of the associated mRNA. Comparison with the binding mode of eIF4G to eIF4E suggests that Cup and eIF4G binding would be mutually exclusive at both binding sites. This shows how a common molecular surface of eIF4E might recognize different proteins acting at different times in the same pathway. The structure provides insight into the mechanism by which Cup disrupts eIF4E-eIF4G interaction and has broader implications for understanding the role of 4E-BPs in translational regulation. Crystal structure of a minimal eIF4E-Cup complex reveals a general mechanism of eIF4E regulation in translational repression.,Kinkelin K, Veith K, Grunwald M, Bono F RNA. 2012 Sep;18(9):1624-34. Epub 2012 Jul 25. PMID:22832024[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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