Messenger RNA Structure Regulates Translation Initiation: A Mechanism Exploited from Bacteria to Humans

T initiation is a major rate-limiting step in protein synthesis and is highly regulated in all cells. Messenger RNAs (mRNAs) play a central role in directing this regulation. Through instructions that remain largely cryptic, mRNA transcripts modulate the initiation process to achieve a specific translation efficiency (TE), the amount of protein made from a given mRNA transcript. TE is precisely tuned, can vary significantly depending on cell type, varies by orders of magnitude across different transcripts, and thus constitutes an essential variable in gene expression. Understanding how mRNAs encode their own unique TEs is therefore a fundamental challenge in biology. Classic studies have shown that mRNAs can encode TE by folding into structures that facilitate or impede translation initiation. The mRNA-binding cleft of the ribosome can accommodate only single-stranded mRNA. Thus, translation initiation requires unfolding of any mRNA structures that overlap the start codon, imposing a structure-dependent energetic penalty on initiation (Figure 1). Synthetic biologists have harnessed these principles to tune the TEs of designed mRNAs over a large dynamic range.