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Publication Abstract from PubMed

Viruses have transformed our understanding of mammalian RNA processing, including facilitating the discovery of the methyl-7-guanosine (m(7)G) cap on the 5' end of RNAs. The m(7)G cap is required for RNAs to bind the eukaryotic translation initiation factor eIF4E and associate with the translation machinery across plant and animal kingdoms. The potyvirus-derived viral genome-linked protein (VPg) is covalently bound to the 5' end of viral genomic RNA (gRNA) and associates with host eIF4E for successful infection. Divergent models to explain these observations proposed either an unknown mode of eIF4E engagement or a competition of VPg for the m(7)G cap-binding site. To dissect these possibilities, we resolved the structure of VPg, revealing a previously unknown 3-dimensional (3D) fold, and characterized the VPg-eIF4E complex using NMR and biophysical techniques. VPg directly bound the cap-binding site of eIF4E and competed for m(7)G cap analog binding. In human cells, VPg inhibited eIF4E-dependent RNA export, translation, and oncogenic transformation. Moreover, VPg formed trimeric complexes with eIF4E-eIF4G, eIF4E bound VPg-luciferase RNA conjugates, and these VPg-RNA conjugates were templates for translation. Informatic analyses revealed structural similarities between VPg and the human kinesin EG5. Consistently, EG5 directly bound eIF4E in a similar manner to VPg, demonstrating that this form of engagement is relevant beyond potyviruses. In all, we revealed an unprecedented modality for control and engagement of eIF4E and show that VPg-RNA conjugates functionally engage eIF4E. As such, potyvirus VPg provides a unique model system to interrogate eIF4E.

Structural studies of the eIF4E-VPg complex reveal a direct competition for capped RNA: Implications for translation.,Coutinho de Oliveira L, Volpon L, Rahardjo AK, Osborne MJ, Culjkovic-Kraljacic B, Trahan C, Oeffinger M, Kwok BH, Borden KLB Proc Natl Acad Sci U S A. 2019 Nov 11. pii: 1904752116. doi:, 10.1073/pnas.1904752116. PMID:31712417^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.