Free protein controls the onset of protein fibril formation under the effect of kinetic stabilization. ARTICULO ENVIADO PARA SU PUBLICACION

PAGANO, R.S; LÓPEZ MEDUS, M.; GÓMEZ, G.E; CARAMELO, J.J.

BIOPHYSICAL JOURNAL

CELL PRESS

Año: 2011

0006-3495

Protein aggregation has been linked to over twenty human pathologies, includingAlzheimer and Parkinson diseases. The mechanisms responsible for the deleteriouseffects of these aggregates and the structural features of the toxic species are not clear. Ithas been suggested that the most dangerous species are not the mature fibrils but insteadthe oligomeric forms generated at the first stages of the aggregation process. In thisscenario, therapeutic strategies aimed to break the fibrils may produce detrimentaleffects, since they could increment the amount of smaller and potentially more toxicspecies. An alternative approach is to inhibit the initial formation of the oligomericspecies. One possible strategy is known as kinetic stabilization. This methodologyemploys small drugs that stabilize the native state, thus incrementing the kinetic barrierfor its conversion to an aggregation prone conformation. In this regard, thosecompounds with higher affinities for the native state usually display higher inhibitoryeffects of amyloid formation. Even though this is a promising strategy, the smallamount of protein left unbound in the presence of these drugs could eventually lead toprotein aggregation. By using a set of natural inhibitors of lysozyme activity we foundthat free protein dictates the extent of aggregation lag times. In addition, we found thatligand-bound protein exerts a reservoir effect that extends the aggregation process.These observations could provide a rationale to predict and control the evolution ofthese therapeutic strategies.