Intrinsically Unstructured Sequences in the mRNA 3? UTR Reduce the Ability of Poly(A) Tail to Enhance Translation

The 5' cap and 3' poly(A) tail of mRNA are known to synergistically stimulate translation initiation via the formation of the cap center dot eIF4E center dot eIF4G center dot PABP center dot poly(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 cap center dot eIF4E center dot eIF4G center dot PABP center dot poly(A) complex and enhance cap-poly(A) translational synergy. Here, we test this hypothesis by introducing intrinsically unstructured sequences into the 5' or 3' UTRs of model mRNAs. We found that the introduction of unstructured sequences into the 3' UTR, but not the 5' UTR, decreases mRNA translation in cellfree 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 3' UTR enhances the cap-poly(A) synergy in translation initiation. (c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Adding unstructured sequences to the 3'UTR of mRNA decreases translation, resulting in a weakened ability of the poly(A) tail.