CONICET | Buscador de Institutos y Recursos Humanos

The conformational disorders are a wide group ofpathologies characterized by the accumulation of protein aggregates thatultimately affect the normal cell function. They include the diseases caused byprions, Alzheimer, Parkinson, and Huntington disease, tauopathies, amiotroficlateral sclerosis, diabetes, nonalcoholic steatohepatitis, etc. Although theidentity of the proteins with altered conformations is different for eachdisease, recent studies show that the molecular mechanisms of the diseasepropagation share large similarities. We previously extensively investigatedthe mechanism by which the phosphoinositide-dependent protein kinase-1 (PDK1) recognizesa specific conformation of its substrates and after modification by PDK1, thesubstrates change their conformation, stabilizing an active form that it is notlonger recognized by PDK1. PDK1 is therefore a conformational sensor that helpsthe target proteins reach its final mature conformation. We postulate that conformationalsensor proteins acting in a similar way to PDK1 may have a key role in themolecular mechanism of conformational diseases (Biondi, R. M. (2004).TrendsBiochem. Sci. 29(3): 136-142). Theinclusion of conformational sensors in the conformational disease model canexplain the existence and propagation of ?strains?. As a model, we investigatethe effect of blocking the conformational sensor pocket in PDK1 (thePIF-pocket), and its effect on the aggregation of PDK1 substrates. We present astrategy to identify conformational sensors that may be key partners in thepropagation of neurodegenerative and/or metabolic conformational diseases. Theidentification of conformational sensors in conformational diseases wouldimprove our understanding of these pathologies and would enable new approachesto prevent or stop the advance of these devastating diseases.