Regulation and aggregation of intrinsically disordered peptides

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (9), p.2758-2763
• Main Authors: Levine, Zachary A., Larini, Luca, LaPointe, Nichole E., Feinstein, Stuart C., Shea, Joan-Emma
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cells; Experiments; Humans; Methylamines - chemistry; Molecular Dynamics Simulation; Peptides; Peptides - chemistry; Physiology; Protein Aggregation, Pathological; Protein Structure, Secondary; Proteins; Simulation; tau Proteins - chemistry; Urea - chemistry
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1418155112

Significance The microtubule-regulating protein tau is a prototypical intrinsically disordered protein (IDP) that plays an important physiological role in the human body; however, aggregates of tau are a pathological hallmark of Alzheimer’s disease. Here we demonstrate through simulations and experiments with an aggregating tau fragment that cosolvent interactions can significantly affect the balance between hydrogen bonds and salt bridge formation in IDPs, subsequently determining their preferred conformations. These subtle perturbations can dramatically shift IDPs from compact ensembles to extended ones, thereby influencing aggregate formation. These results lend considerable insight into the biophysics of the regulation and aggregation of IDPs. Intrinsically disordered proteins (IDPs) are a unique class of proteins that have no stable native structure, a feature that allows them to adopt a wide variety of extended and compact conformations that facilitate a large number of vital physiological functions. One of the most well-known IDPs is the microtubule-associated tau protein, which regulates microtubule growth in the nervous system. However, dysfunctions in tau can lead to tau oligomerization, fibril formation, and neurodegenerative disease, including Alzheimer’s disease. Using a combination of simulations and experiments, we explore the role of osmolytes in regulating the conformation and aggregation propensities of the R2/wt peptide, a fragment of tau containing the aggregating paired helical filament (PHF6*). We show that the osmolytes urea and trimethylamine N-oxide (TMAO) shift the population of IDP monomer structures, but that no new conformational ensembles emerge. Although urea halts aggregation, TMAO promotes the formation of compact oligomers (including helical oligomers) through a newly proposed mechanism of redistribution of water around the perimeter of the peptide. We put forth a “superposition of ensembles” hypothesis to rationalize the mechanism by which IDP structure and aggregation is regulated in the cell.