Programmed −1 Frameshift of a Ribosome: Non-Monotonic Variation of Frameshift Efficiency with Increasing Stiffness of mRNA Secondary Structure

Abstract

A ribosome is a molecular motor [1] that synthesises a polypeptide using a mRNA template that also serves as a track for its motor-like directed movement in steps of three nucleotides (a codon). However, on some special “slippery” sequence of nucleotides on the mRNA the reading frame of a ribosome can shift backward by one nucleotide which is identified as a −1 programmed frameshift. In addition to the slippery sequence, a secondary structure of the mRNA strand (for example, a pseudo knot), located downstream from the slippery sequence, is also essential for programmed −1 frameshift. Since the shifted reading frame picks up a sequence of amino acids that is, in general, different from the sequence that would have been selected by the unshifted original reading frame, a ribosome that resumes protein synthesis after such a frameshift produces a fusion protein. Often many ribosomes simultaneously move along the same mRNA track, all synthesising identical polypeptides. The stiffness of the mRNA secondary structure determines the extent of ribosomal crowding in the mRNA segment upstream from that structure. Using a theoretical model we demonstrate how the increasing stiffness of the secondary structure of the mRNA causes increasing crowding of the ribosomes that, in turn, leads to a non-monotonic variation of the efficiency of frameshift [3]. Our numerical estimates indicate that the novel phenomenon predicted by our theoretical model can be tested experimentally by ribosome profiling technique [4]. [1] D. Chowdhury, Biophys. J. 104, 2331 (2013). [2] J.F. Atkins and R.F. Gesteland (eds.) Recoding: Expansion of Decoding Rules Enriches Gene Expression, (Springer, 2010). [3] B. Mishra and D. Chowdhury, to be published (2015). [4] N.T. Ingolia, Nat. Rev. Genet. 15, 205 (2014).