Role of mRNA structure in the control of protein folding

Abstract

Specific structures in mRNA modulate translation rate and thus can affect protein folding. Using the protein structures from two eukaryotes and three prokaryotes, we explore the connections between the protein compactness, inferred from solvent accessibility, and mRNA structure, inferred from mRNA folding energy (ΔG). In both prokaryotes and eukaryotes, the ΔG value of the most stable 30 nucleotide segment of the mRNA (ΔGmin) strongly, positively correlates with protein solvent accessibility. Thus, mRNAs containing exceptionally stable secondary structure elements typically encode compact proteins. The correlations between ΔG and protein compactness are much more pronounced in predicted ordered parts of proteins compared to the predicted disordered parts, indicative of an important role of mRNA secondary structure elements in the control of protein folding. Additionally, ΔG correlates with the mRNA length and the evolutionary rate of synonymous positions. The correlations are partially independent and were used to construct multiple regression models which explain about half of the variance of protein solvent accessibility. These findings suggest a model in which the mRNA structure, particularly exceptionally stable RNA structural elements, act as gauges of protein co-translational folding by reducing ribosome speed when the nascent peptide needs time to form and optimize the core structure.

Codon bias confers stability to humanmRNAs

“…There are many factors that can affect ribosome profiling results such as growth conditions, coverage, cloning and sequencing biases, methods of bioinformatics analysis, and experimental noise [18,52,53]. Importantly, these structures may serve to reduce ribosome speed when the nascent peptide requires additional time to fold to its correct conformation [58]. Additionally, our study along with others' suggests that slower elongation of ribosome is a key feature of mRNA stability.…”

“…These obstacles for ribosome elongation are reversible and dynamically regulated by RNA helicases [56,57]. Importantly, these structures may serve to reduce ribosome speed when the nascent peptide requires additional time to fold to its correct conformation [58]. Furthermore, it has been shown in Neurospora that codon usage can regulate co-translational protein folding and, subsequently, its function [59].…”

STUB1polyadenylation signal variant AACAAA does not affect polyadenylation but decreasesSTUB1translation causing SCAR16

“…Polyadenylation signal AATAAA is the best known of all regulatory elements in the 3 ′ UTR of mammalian mRNA and is required for efficient termination of transcription, cleavage at a specific site downstream of the signal, and addition of generally 150-250 adenosine nucleotides to the 3 ′ end (Bienroth, Keller, & Wahle, 1993;Guhaniyogi & Brewer, 2001). The poly(A) tail has a role in mRNA stability and translation efficiency (Faure, Ogurtsov, Shabalina, & Koonin, 2016;Yang et al, 2003). Polyadenylation signal sequence is highly conserved in human genes.…”

“…Other sequences in the 3 ′ UTR can play roles in various posttranscriptional regulation mechanisms including stability, nuclear transport, and subcellular localization (Kislauskis, Li, Singer, & Taneja, 1993). Some of those functions are hypothesized to mainly depend on the secondary structure of the molecule, for example, by rendering cis elements such as target sequences of miRNAs more exposed (Haas, Sczakiel, & Laufer, 2012) or impairing the rate of translation (Faure et al, 2016). Thus, sequence alterations in the 3 ′ UTRs of many genes have been reported to lead to disease.…”

“…Another mechanism is that altered mRNA secondary structure affects the ribosomal speed, which in turn causes the nascent peptide to fold differently (Faure et al, 2016;Kaiser, Goldman, Chodera, Tinoco, & Bustamante, 2011). Misfolded proteins are usually degraded.…”