Selected article for: "cap structure and mRNAs translation"
Author: Renata C Fleith; Harriet V Mears; Edward Emmott; Stephen C Graham; Daniel S Mansur; Trevor R Sweeney
Title: IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA
  • Document date: 2018_2_8
    • ID: j97gul0w_3
    Snippet: TPR motifs are frequently involved in protein-protein interactions and are commonly found in scaffolding proteins (11) . The crystal structures of IFIT1 and IFIT5 revealed a positively charged pocket formed in the groove between the N and C domains that interacts with single-stranded RNA (8) (9) (10) . IFIT1 RNA binding activity was first reported by Pichlmair et al. (12) who identified proteins in lysates from IFN stimulated cells that interacte.....
    Document: TPR motifs are frequently involved in protein-protein interactions and are commonly found in scaffolding proteins (11) . The crystal structures of IFIT1 and IFIT5 revealed a positively charged pocket formed in the groove between the N and C domains that interacts with single-stranded RNA (8) (9) (10) . IFIT1 RNA binding activity was first reported by Pichlmair et al. (12) who identified proteins in lysates from IFN stimulated cells that interacted with 5´-ppp RNAs. Subsequently, we and others demonstrated that IFIT1 tightly binds capped RNAs lacking methylation on the first cap-proximal nucleotide (cap0) with low nanomolar affinity (13) (14) (15) . While similar positively charged tunnels in IFIT1 and IFIT5 interact with the phosphate backbone of bound RNAs (8, 9, 13) , only IFIT1 possesses a large hydrophobic cavity at the rear of the tunnel that can accommodate the cap structure (9) . These findings support a model whereby IFIT1 out-competes eukaryotic initiation factor (eIF) 4E/4F for binding to cap0-mRNAs, thereby inhibiting their translation. As host mRNAs are generally methylated on the first or first and second bases (cap1 and cap2, respectively), this selectivity offers a mechanism of recognising and blocking translation of non-self RNAs.

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