Regulation and aggregation of intrinsically disordered peptides

Abstract

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.protein folding | intrinsically disordered proteins | molecular dynamics simulations | osmolytes | tau protein M ost proteins in the human body have a well-defined, stable three-dimensional structure that is intimately tied to their physiological function. In the past few decades however, researchers have also identified a class of proteins that are natively unstructured. The latter, often referred to as intrinsically disordered proteins (IDPs) (1), are widespread and have the ability to quickly change their conformations to participate in a variety of biological processes. IDPs typically contain multiple charged side chains and few hydrophobic residues. Despite these characteristics, IDPs are not typically found in extended states but rather populate compact states due to hydrogen bonds and salt bridges (2, 3). IDP structures are highly regulated in the cell, and aberrant regulation often results in protein aggregation.In this paper we consider the effect of external agents, specifically osmolytes, in regulating IDP structure and aggregation properties. To carry out this study, we focused on the microtubule-associated protein tau, a soluble (4), archetypical IDP found in the nervous system that helps regulate and stabilize microtubules (5, 6). When the regulation of tau structure and activity is compromised, tau loses its ability to bind to microtubules, and disassociated tau proteins can aggregate into supramolecular assemblies with a cross-β structure (7-9) typical of amyloid fibers. This aggregation process is a pathological hallmark of Alzheimer's disease and other forms of dementia known as tauopathies (10, 11). We consider here a segment of tau, the R2/wt fragment 273 GKVQIINKKLDL 284 , which contains the highly aggregation ...

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

“…Consistently, a recent study of ( 273 GKVQIINKKLDL 284 ) peptide has shown that the balance between hydrogen bonds and salt bridge formation in IDPs can dramatically shift IDPs from compact ensembles to extended ones. 37 The observed behavior could be the first step of Aβ cross-seeding tau into prion-like aggregation. Contrary to common intuition that Aβ's cross-seeding of tau will enhance tau's beta structure content, it is more likely that Aβ first stretches tau into more open states permitting intermolecular stacking that will finally aggregate into fibril.…”

Protein folding and stability in the presence of osmolytes

“…Such proteins can form compact regular structures only during interactions with their partners [102]. A number of studies have indicated the possibility that native disordered proteins can assume a compact regular structure in osmolyte solutions without interacting with their corresponding partners [66,[103][104][105][106]. As an example, a study on RNAse P [66] uncovered the fact that the native protein structure in a complex with RNA and the structure that emerges during renaturation of this protein in TMAO solution are similar but not identical, while the paths by which this protein folds in the presence of RNA and it is absence, but in the presence of TMAO, are considerably different.…”

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

“…1A, Left). Although Tau strongly binds to the MT surface (∼1-3 μM affinity) (10,26), recent work suggests that Tau-MT interactions are highly dynamic and that Tau can assume numerous structures (30,31).…”