Intrinsic disorder modulates protein self-assembly and aggregation

Abstract

Protein molecules have evolved to adopt distinctive and welldefined functional and soluble states under physiological conditions. In some circumstances, however, proteins can self-assemble into fibrillar aggregates designated as amyloid fibrils. In vivo these processes are normally associated with severe pathological conditions but can sometimes have functional relevance. One such example is the hydrophobins, whose aggregation at air-water interfaces serves to create robust protein coats that help fungal spores to resist wetting and thus facilitate their dispersal in the air. We have performed multiscale simulations to address the molecular determinants governing the formation of functional amyloids by the class I fungal hydrophobin EAS. Extensive samplings of full-atom replica-exchange molecular dynamics and coarse-grained simulations have allowed us to identify factors that distinguish aggregation-prone from highly soluble states of EAS. As a result of unfavourable entropic terms, highly dynamical regions are shown to exert a crucial influence on the propensity of the protein to aggregate under different conditions. More generally, our findings suggest a key role that specific flexible structural elements can play to ensure the existence of soluble and functional states of proteins under physiological conditions. amyloid formation | protein aggregation | protein dynamics T he identification of the factors that enable proteins and macromolecules to remain functional and soluble under physiological conditions is of central importance in biology (1). The ability to avoid inappropriate protein aggregation is a distinctive property of all functional biological macromolecules and assumes a particularly crucial role in disfavoring aberrant processes such as those involving protein self-assembly into highly organized amyloid fibrils; these latter processes are associated with a range of severe pathological conditions, including neurodegenerative disorders such as Alzheimer's and Parkinson diseases and a number of nonneuropathic conditions including type II diabetes (2-4). In vivo, amyloid formation is largely pathogenic, although in some cases it can have functional relevance, as for example in the storage of peptide hormones in mammals (5) or the response to nutrient depletion conditions in yeast (6). It has become apparent, however, that the ability to form amyloid structures is a common characteristic of polypeptide chains in vitro (7); this finding begs the question of how the majority of the peptides and proteins in a living system are able to suppress such processes under normal circumstances.It is well established that there are multiple strategies within biological organisms to inhibit aberrant protein aggregation, including the regulation of protein expression levels (8) and the existence of quality control mechanisms to detect and degrade misfolded conformations (9-12). The principal means for controlling misfolding and aggregation are, however, intrinsic factors that proteins have optimized throughout evolu...

Chaperone activation by unfolding

“…As a result, amino acid sequences, in the absence of any selection, are expected to devolve rapidly into disorder. Although there are many good reasons to think that disorder can play an important role in proteins (20,52,53), firmly establishing a functional role for disorder has been experimentally difficult. As a conditionally disordered protein, HdeA opens up a unique approach to dissecting the contribution of disorder to protein function.…”

Macromolecular structures probed by combining single-shot free-electron laser diffraction with synchrotron coherent X-ray imaging

“…Long polypeptide chains of biological molecules, similar to polymers, are intrinsically designed to fold to form globular structures to decrease surface energy by increasing molecular bonds 40 . Such self-assembled macromolecular complexes formed from long-chained polymers share similar features of lamellar extensions, radial growth and so on, generally termed as a spherulite 41 .…”

Complex Molecules at Liquid Interfaces: Insights from Molecular Simulation

“…As shown by Schulz et al [65] this change in conformational behaviour can strongly influence the potential application of these proteins, specifically finding that EAS (a class-I hydrophobin) induced the formation of hydroxyapatite at water-hexane interface, whereas HFBII did not, which can be explained by the larger conformational change exhibited by EAS at the interface and in the presence of Ca 2+ and HPO 4 − ions. Simulation of EAS [66] using a multiscale model also showed that its conformational change is responsible for the aggregation of these proteins into fibrils, underlining the importance of accurately representing conformational change in these proteins. Going beyond hydrophobins, Euston has also compared atomistic and coarse-grain models for the simulation of proteins at fluid interfaces [67], finding that CG models gave results similar to atomistic models, although the CG model used underestimated the penetration of the protein (Barley LTP) into the oil phase.…”