The shape of mRNA

Question

I was wondering about the shapes assumed by mRNA. I have read some sources quoting that it is linear (quora, so not very reliable) and also a source that says a hairpin shape is common (nature, so I would rather go with this one).

I was also wondering what additional factors or features ensure the mRNA has this shape. For instance, the first source says that the mRNA 'is linear so that the ribosomes can bind to it'. But, clearly, all that is required for this is that the ribosome binding site is exposed. In that case, the remainder of the mRNA may either spontaneously unravel as it is being translated, or there may be something slightly more specific taking place catalysed by the ribosome, or there may be an additional enzyme that associates and catalyses the unfolding of the mRNA as it is being translated.

The thing is, I just find it difficult to belive that the mRNA would not fold up on itself, but on the other hand if it did, perhaps it would be too stable and would not be degraded sufficiently easily. We would have accmulation of mRNA in the cell, unless there was a protein that specifically degraded it.

My only other hypothesis, if it truly is the case that the mRNA does not fold up, is that it is down to the DNA in the nucleaus being 'too dense' to permit the mRNA folding in the nucleus, and once it exits via a nuclear pore it is immediately being translated and forming a polyribosome complex. So then it can no longer fold.

I do not think that the DNA content in the nucleus is sufficiently dense for steric effects like this. I have seen electron micrograph images in a book (Molecular Biology of the Cell) of mRNA exiting a nuclear pore. It seems quite coiled up. Unfortunately, I have been unable to find a clear representative image online or the associated paper. But perhaps the mRNA can coil up in the nucleus, but is straightened out as it is pulled throught the nuclear pore. Proteins and factors associated with the nuclear pore may catalyse the breaking of the hydrogen bonds.

Any details on this would be much appreciated.

Answer 1

Unfortunately it is often taught that mRNA is linear, but this is not true at all. Nucleotides within mRNA can form intra-molecular hydrogen bonds with other nucleotides, creating secondary structures, interactions between these secondary structures results in tertiary structures. mRNAs have highly variable secondary structures, primarily due to differences in the sequence of the ORF, so there is not a consensus structure adopted by mRNAs. However, codon degeneracy is important in producing more ordered and stable mRNA secondary structures in ORFs, resulting in increased mRNA half-life. Nucleotides in positions one and two in codons are the most conserved, whereas the third nucleotide position is the least conserved and has elevated GC content, thus making the greatest contribution to the stability of the secondary structure. The 5’ UTR typically contains lots of secondary structures, which may help in modulation of translation initiation, whereas 3’ UTRs contain fewer secondary structure, resulting in structural instability around binding sites for proteins and miRNAs, enhancing miRNA and protein binding. The start and stop codons are less frequently base-paired than the rest of the mRNA, suggesting they exist in local secondary structures which lead to efficient initiation and termination of translation. However, the sequence immediately downstream of the stop codon has a high GC content and an in increase in frequency of base pairing. It has been hypothesised that this strong secondary structure is present to interrupt post-termination ribosomal scanning. Whilst increasing stability of mRNA increases half-life, low secondary structures around binding sites within the mRNA suggests that thermodynamic stability of mRNA is optimised and not-minimised in all scenarios.

With regards to translation initiation there is quite a lot of cool work on dynamic secondary RNA structures for regulating translation initiation, this work primarily revolves around riboregulators and riboswitches. I won't go into detail about them here, but for a great paper on riboregulators see: Green, A. A., Silver, P. A., Collins, J. J. & Yin, P. Toehold switches: de-novo-designed regulators of gene expression. Cell 159, 925–39 (2014)

References:

Comparative analysis of orthologous eukaryotic mRNAs: potential hidden functional signals. Nucleic Acids Res. 32, 1774–82 (2004).Shabalina, S. A., Ogurtsov, A. Y., Rogozin, I. B., Koonin, E. V & Lipman, D. J.

Duan, J. & Antezana, M. A. Mammalian Mutation Pressure, Synonymous Codon Choice, and mRNA Degradation. J. Mol. Evol. 57, 694–701 (2003).

Shabalina, S. A., Ogurtsov, A. Y. & Spiridonov, N. A. A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res. 34, 2428–2437 (2006).