The Dynamism of Intrinsically Disordered Proteins: Binding-Induced Folding, Amyloid Formation, and Phase Separation

Mukhopadhyay, Samrat

doi:10.1021/acs.jpcb.0c07598

Cited by 42 publications

(43 citation statements)

References 139 publications

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“…Intrinsically disordered proteins/regions (IDPs/IDRs) have emerged as the major drivers of intracellular liquid–liquid phase separation (LLPS) into membrane‐less organelles 93–95 . IDPs belong to the class of proteins that do not possess defined tertiary conformations and they adopt an ensemble of structures sampling a wide range of conformational space 96,97 . It is their structural plasticity that enables them to potentially engage in various biological functions such as cell signaling, transport, and so forth 98 .…”

Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

“…For instance, fluorescence recovery after photo‐bleaching (FRAP) kinetics and fluorescence correlation spectroscopy can be used to study the translational diffusion of proteins within the condensates. In addition, fluorescence anisotropy measurements can offer important insights into the rotational dynamics and backbone dihedral mobility of IDPs on the picosecond to nanosecond timescales 97 . These studies suggested that high intrinsic disorder, flexibility, and mobility are present in the condensed phase of tau (Figure 5).…”

Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

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Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

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Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase‐separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid‐like membrane‐less compartments. However, aberrant phase transitions into gel‐like or solid‐like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule‐associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid‐to‐solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one‐component and complex multi‐component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length‐ and time‐scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.

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Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

Section: Physical Chemistry Of Tau Llpsmentioning

confidence: 99%

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

et al. 2021

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“…Our recent work dissected the molecular mechanism of heterotypic intermolecular association of two structurally distinct, prefibrillar (A11-positive) and fibrillar Aβ42 oligomers (OC-positive) with the recombinant human prion protein (PrP) (Figure 4). 92,93 Using an array of biophysical and biochemical tools, we demonstrated that the intrinsically disordered N-terminal segment of PrP harboring residue 99 is the principle binding region for the interaction with Aβ oligomers, which recruits the two conformationally distinct Aβ oligomers via electrostatic interaction. Our binding equilibrium studies, along with the binding kinetics, showed that the OC-positive Aβ oligomers have a stronger binding affinity to PrP than the A11-positive Aβ oligomers.…”

Section: Cellular Prion Protein (Prp C )mentioning

confidence: 99%

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

Madhu

Mukhopadhyay

2021

J of Cellular Biochemistry

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Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformationspecific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl-D-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.

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“…Although these methods are useful to study LLPS on the molecular basis, the structural analyses are restricted to the equilibrium states due to their low time resolutions. Other methods such as small angle X-ray scattering (SAXS), atomic force microscopy (AFM), and fluorescence resonance energy transfer (FRET) have been used to investigate the conformational heterogeneities of IDRs ( Mukhopadhyay, 2020 ; Surewicz and Babinchak, 2020 ; Bari and Prakashchand, 2021 ; Kodera et al, 2021 ). However, there are several difficulties to study the LLPS processes by these methods, although the time resolutions of them have been improved.…”

Section: Introductionmentioning

confidence: 99%

A Time-Resolved Diffusion Technique for Detection of the Conformational Changes and Molecular Assembly/Disassembly Processes of Biomolecules

Nakasone

Terazima

2021

Front. Genet.

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Biological liquid–liquid phase separation (LLPS) is driven by dynamic and multivalent interactions, which involves conformational changes and intermolecular assembly/disassembly processes of various biomolecules. To understand the molecular mechanisms of LLPS, kinetic measurements of the intra- and intermolecular reactions are essential. In this review, a time-resolved diffusion technique which has a potential to detect molecular events associated with LLPS is presented. This technique can detect changes in protein conformation and intermolecular interaction (oligomer formation, protein-DNA interaction, and protein-lipid interaction) in time domain, which are difficult to obtain by other methods. After the principle and methods for signal analyses are described in detail, studies on photoreactive molecules (intermolecular interaction between light sensor proteins and its target DNA) and a non-photoreactive molecule (binding and folding reaction of α-synuclein upon mixing with SDS micelle) are presented as typical examples of applications of this unique technique.

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The Dynamism of Intrinsically Disordered Proteins: Binding-Induced Folding, Amyloid Formation, and Phase Separation

Cited by 42 publications

References 139 publications

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

A Time-Resolved Diffusion Technique for Detection of the Conformational Changes and Molecular Assembly/Disassembly Processes of Biomolecules

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