ABSTRACT
Abstract-The family of conformational diseases is expanding rapidly, including not only neurodegenerative conditions like Alzheimer's and Parkinson's diseases, but also certain autoimmune diseases and cancers. The corresponding pathologies have in common their link to misfolded proteins, which accumulate in the cytosol, the rough ER or built up extracellularily, thereby inducing apoptosis, abolishing cell to cell communication, eliciting the immune response or cancelling proper enzymatic (i.e. tumour suppressor) activities. Understanding the mechanism leading to protein misconformation is essential for early diagnosis, efficient therapy and reliable prognosis of these devastating conditions. In previous articles, we showed that, in addition to the primary sequence, an important determinant of the protein structure is the local translation rate, controlled mainly by the choice of synonymous codons along the coding sequence. We found that in coding sequences of E. coli, amino acids having a propensity to appear in particular secondary structures are located in surroundings strongly constraint in fast, or slowly translated codons. To extend this observation to other species, we analyse here all ribosomal protein genes in four species (H. sapiens, S. cerevisiae, B. subtilis and E. coli), for constraints of particular amino acids within sequences of 5 to 21 codons, translated fastest or slowest on average. Although the species investigated make rather different usage of synonymous codons, each species utilizes its synonymous codon repertoire so as to achieve amino-acid constraints in these sequences similar to those observed in E. coli. This suggests that the amino-acid constraints within gene sequences translated at extreme rates are biological invariants to which the species have to conform. Although the constraints are more relaxed in sequences translated at less extreme rates, the general conclusion is that the local translation rate makes, at places at least, important contributions to the protein conformation. Conversely, modifications the local translation rate can at places interfere with native folding and lead to misfolding. Such modifications could be the consequence of spontaneous defects in the translation machinery of the cell, or of its unscheduled, excessive solicitation. This may be one of the routes to conformational diseases.
