Targeting disordered proteins with small molecules using entropy

Heller, Gabriella T.; Sormanni, Pietro; Vendruscolo, Michele

doi:10.1016/j.tibs.2015.07.004

Cited by 100 publications

(121 citation statements)

References 53 publications

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“…For fibrillogenesis, Aβ monomers need to adopt a specific conformation to bind to a growing fibre [57][58][59]; however, Zn 2+ may rapidly exchange between Aβ peptides, altering the population of conformations typically available to them, and restricting the population of the necessary fibre forming conformation. This metal ion induced entropic expansion of conformational space, for disordered proteins, has recently been described [60]. A fourth possibility would be that Zn 2+ binding promotes the formation of a unique seed, which may direct downstream Aβ aggregation through a template mechanism, however our seeding experiment (Fig.…”

Section: Discussionmentioning

confidence: 50%

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

Matheou

Younan

Viles

2016

Journal of Molecular Biology

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The misfolding and self-assembly of amyloid-β (Aβ) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn(2+) homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models. Here, we investigate how the kinetics of Aβ fibre growth are affected at a range of Zn(2+) concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for Aβ(1-40), and Aβ(1-42), as little as 0.01mol equivalent of Zn(2+) (100nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, Aβ(1-40) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas Aβ(1-42) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn(2+) ions are able to influence a great many Aβ molecules through the rapid exchange of Zn(2+) between Aβ peptides. Surprisingly, although Cu(2+) binds to Aβ 10,000 times tighter than Zn(2+), the effect of Zn(2+) on Aβ assembly dominates in Cu(2+)/Zn(2+) mixtures, suggesting that trace levels of Zn(2+) must have a profound effect on extracellular Aβ accumulation. Trace Zn(2+) levels profoundly influence Aβ assembly even at concentrations weaker than its affinity for Aβ. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact.

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Section: Discussionmentioning

confidence: 50%

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

Matheou

Younan

Viles

2016

Journal of Molecular Biology

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“…This behavior is in contrast to several models in which small molecules are proposed to interact with an ensemble of conformations and that small molecule:IDP interactions expand the conformational landscape of the IDP creating new conformations. 4–6 We propose that the SJ403 small molecule binds preferentially to clusters of distal aromatic residues, including W60 and W76, and that these interactions lead to the displacement of Y88 that otherwise transiently engages the two tryptophan residues within these clusters (Figure 4). It is possible that different small molecules and IDPs utilize fundamentally different mechanisms when they interact.…”

Section: Discussionmentioning

confidence: 99%

A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein

Ban¹,

Iconaru²,

Ramanathan

et al. 2017

J. Am. Chem. Soc.

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Intrinsically disordered proteins (IDPs) have roles in myriad biological processes and numerous human diseases. However, kinetic and amplitude information regarding their ground-state conformational fluctuations have remained elusive. We demonstrate using nuclear magnetic resonance (NMR)-based relaxation dispersion that the D2 domain of p27Kip1, a prototypical IDP, samples multiple discrete, rapidly exchanging conformational states. By combining NMR with mutagenesis and small angle X-ray scattering (SAXS), we show that these states involve aromatic residue clustering through long-range hydrophobic interactions. Theoretical studies have proposed that small molecules bind promiscuously to IDPs, causing expansion of their conformational landscapes. However, based on previous NMR-based screening results, we show here that compound binding only shifts the populations of states that existed within the ground-state of apo p27-D2 without changing the barriers between states. Our results provide atomic resolution insight into how a small molecule binds an IDP and emphasize the need to examine motions on the low microsecond timescale when probing these types of interactions.

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“…When considering binding to a single protein site, these interactions are likely to be weak due to the need to overcome the high conformational entropy cost associated with binding disordered polypeptide chains. However, it has been proposed that small molecules or ions that bind promiscuously to multiple sites within a disordered protein can increase the entropy of the protein ensemble, causing the entropy change of binding to be thermodynamically favorable 414 . Progress has been made in characterizing interactions between non-physiological small molecules and disordered proteins.…”

Section: Interactions Between Disordered Proteins and Small Moleculesmentioning

confidence: 99%

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

et al. 2016

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Understanding signaling and other complex biological processes requires elucidating the critical roles of intrinsically disordered proteins and regions (IDPs/IDRs), which represent ~30% of the proteome and enable unique regulatory mechanisms. In this review we describe the structural heterogeneity of disordered proteins that underpins these mechanisms and the latest progress in obtaining structural descriptions of ensembles of disordered proteins that are needed for linking structure and dynamics to function. We describe the diverse interactions of IDPs that can have unusual characteristics such as “ultrasensitivity” and “regulated folding and unfolding”. We also summarize the mounting data showing that large-scale assembly and protein phase separation occurs within a variety of signaling complexes and cellular structures. In addition, we discuss efforts to therapeutically target disordered proteins with small molecules. Overall, we interpret the remodeling of disordered state ensembles due to binding and post-translational modifications within an expanded framework for allostery that provides significant insights into how disordered proteins transmit biological information.

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Targeting disordered proteins with small molecules using entropy

Cited by 100 publications

References 53 publications

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein

Dynamic Protein Interaction Networks and New Structural Paradigms in Signaling

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