Proline to the rescue

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Protein misfolding is now recognized to be a major contributing factor in a number of protein folding diseases, including amyotropic laterial sclerosis, cystic fibrosis, Alzheimer's disease, Parkinson's disease, and a host of many different amyloidosis diseases. Protein aggregation and misfolding reactions are also the bane of protein production and impede pharmaceutical drug development. Understanding the fundamental in vivo factors that control the kinetics of protein misfolding is the crucial aspect involved in developing procedures and strategies to avoid this deleterious side reaction. Elegant in vivo work of Nollen et al. (1) has shown that the elements controlling protein homeostasis such as protein synthesis, energy production in the cell, chaperone-dependent protein folding, protein transport, and protein degradation collectively control intracellular protein aggregation. However, it is also known that protein folding is influenced by the presence of intracellular osmolytes that, in turn, dramatically affect protein stabilities, protein folding rates, and protein aggregation. Thus, it would be highly useful if we could determine how osmolytes directly influence the kinetics of protein folding and aggregation in vivo. In this issue of PNAS, Ignatova and Gierasch (2) accomplish this feat by using their earlier in vivo protein aggregation cellular retinoic acid binding protein (CRABP) 4′,5′-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FlAsH) model system (3) to monitor in vivo formation of amorphous and fibrillar/amyloid-like aggregation reactions driven by either misfolding or polyglutamine (53htt) aggregation in the presence of high intracellular proline concentrations. Interestingly, they find that the aggregation propensities and kinetics of their particular folding variants of CRABP FlAsH are dramatically altered when proline concentration levels are changed before and during the aggregation reaction (Fig. 1). This system allows these investigators to directly visualize for the first time the in vivo effects of rapid accumulation of an intracellular osmolyte during protein aggregation.