The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain

Sunit Mandad,André Fischer,Henning Urlaub,Stefan Bonn,Tonatiuh Peña Centeno ,Ramón Vidal ,Roya Yousefi ,Ivo Feußner ,Raza‐Ur Rahman ,Koray Kırlı ,Felipe Opazo,Eva Benito,Peter Rehling,Burkhard Rammner,Till Ischebeck,Sven Dennerlein,Hanna Wildhagen,Sarva Keihani,Silvio O Rizzoli,Inga Urban,Eugenio F Fornasiero

doi:10.1038/s41598-018-35277-8

Abstract

The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.

Highlights

Variation in mRNA levels alone is not sufficient to explain the variation in protein abundance[2]
The connections between mammalian sequences and parameters of the protein homeostasis have been suggested to be causal in nature, as indicated by protein expression experiments relying on different synonymous codons, which suggested that the codon bias[14], the mRNA secondary structure[28], and/or the G/C contents[29] may induce changes in protein homeostasis parameters, and/or in the conformation of individual proteins[30,31]
We set out to test whether the amino acid and the codon sequences could predict the different parameters of protein homeostasis in mammals, such as the protein lifetimes, the mRNA and protein abundances, and the translation rates

Summary

Introduction

Variation in mRNA levels alone is not sufficient to explain the variation in protein abundance[2]. Neurons, one of the main cell types in the brain, are long-lived cells with extremely limited self-renewal capacity They require an optimal control of homeostasis to prevent the accumulation of misassembled proteins, or the insufficient production of necessary proteins. Extensive in vivo and ex vivo measurements are feasible in the brain, for parameters such as protein and mRNA abundances, protein lifetimes, and translation rates We performed such measurements, and we found that the protein lifetime, along with other parameters of homeostasis, could be predicted with fairly high precision from the sequences, with the most important sequence parameter being the G/C contents of the third (wobble) nucleotide

Methods

Results

Discussion

Conclusion