ABSTRACT
Abstract-Translation was long thought to be a smooth process, producing invariably native proteins. However, it appeared recently that this may not always be the case. First, a family of apparently unconnected diseases, including important neurodegenerative conditions, like Alzheimer, Parkinson, Huntington, and prion disorders, was shown to be linked to misfolded proteins ('conformational diseases'). Secondly, up to 70% of nascent proteins are recognized as misfolded and tagged for proteolysis whilst still attached to the ribosome. Misfolding seems therefore to be a quite common event, which is however most often corrected by efficient proteolysis of the misconformers produced. Misfolding therefore usually remains unnoticed, and safe when proteolysis is unable to remove the misconformers, which is the case in conformational diseases. Since the latter usually onset in the second half of human life, the mechanism of misfolding is likely to be linked to defects in the cellular translation and proteolysis machinery. This speculation is further substantiated by the observation that the amount of nascent proteins, recognized as misconformers whilst still attached to the ribosome, depends on the cellular state. On the other hand, the large amount of work devoted to prion proteins has highlighted the fact that certain proteins are prone to become easily misfolded. This implies that particular motifs in the primary structure of proteins enter metastable or 'soft' conformations upon synthesis, which can easily flip from one state to another.
