CEO, Kinepict Ltd, Budapest, Hungary
Associate Professor, Semmelweis University, Budapest, Hungary
A detailed picture of how the folding energy landscape of a protein changes as the native structure is gradually destabilised.
Sequence specific partitioning of polypeptides between protein folding, and amyloid formation is of outstanding physiological and pathological importance. Using yeast phosphoglycerate kinase as model, here we identify the features of the energy landscape that decide the fate of the protein: folding or amyloidogenesis. Structure formation was initiated from the acid-unfolded state, and monitored by fluorescence from 10 ms to 25 days. Solvent conditions were gradually shifted between folding and amyloidogenesis, and the properties of the energy landscape governing structure formation were reconstructed. A continuous transition of the energy landscape between folding and amyloid formation was observed. In the early steps of both folding and misfolding, the protein searches through a hierarchically structured energy landscape to form a molten globule on the seconds timescale. Depending on the conditions, this intermediate either folds to the native state in a few minutes, or forms amyloid fibers on the several days and weeks timescale. As conditions are changed from folding to misfolding, the barrier separating the molten globule and native states increases, the barrier to the amyloid decreases. In the meantime the native state also becomes more unstable and the amyloid more stable.
Agócs G, Szabó BT, Köhler G, Osváth S (2012)
Biophysical Journal 102, 2828-2834, Comparing the folding and misfolding energy landscapes of phosphoglycerate kinase.