Intrinsically Unstructured Sequences in the mRNA 3ʹ UTR Reduce the Ability of Poly(A) Tail to Enhance Translation. Issue 24 (30th December 2022)

• Record Type: Journal Article
• Authors: Lai, Wan-Jung C.; Zhu, Mingyi; Belinite, Margarita; Ballard, Gregory; Mathews, David H.; Ermolenko, Dmitri N.
• Is Part Of: Journal of molecular biology. Volume 434:Issue 24(2022)
• Publication Date: 2022-12-30
• Subjects: Cap-poly(A) synergy -- mRNA secondary structure -- translation; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2022.167877
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: The role of mRNA secondary structure in cap-poly(A) translational synergy is unclear. We show that unstructured sequences in the 3′ UTR decrease mRNA translation. Unstructured sequences in the 3′ UTR diminish ability of the poly(A) tail to stimulate translation. Base pair formation by the 3′ UTR enhances cap-poly(A) synergy in translation. Abstract: The 5ʹ cap and 3ʹ poly(A) tail of mRNA are known to synergistically stimulate translation initiation via the formation of the capeIF4EeIF4GPABPpoly(A) complex. Most mRNA sequences have an intrinsic propensity to fold into extensive intramolecular secondary structures that result in short end-to-end distances. The inherent compactness of mRNAs might stabilize the capeIF4EeIF4GPABPpoly(A) complex and enhance cap-poly(A) translational synergy. Here, we test this hypothesis by introducing intrinsically unstructured sequences into the 5ʹ or 3ʹ UTRs of model mRNAs. We found that the introduction of unstructured sequences into the 3ʹ UTR, but not the 5ʹ UTR, decreases mRNA translation in cell-free wheat germ and yeast extracts without affecting mRNA stability. The observed reduction in protein synthesis results from the diminished ability of the poly(A) tail to stimulate translation. These results suggest that base pair formation by the 3ʹ UTR enhances the cap-poly(A) synergy in translation initiation.