Untangling the Conformational Polymorphism of Disordered Proteins Associated With Neurodegeneration at the Single-Molecule Level

Birol, Melissa; Melo, Ana M.

doi:10.3389/fnmol.2019.00309

Cited by 11 publications

(15 citation statements)

References 121 publications

(149 reference statements)

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“…In Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD) characteristic proteins unfold and form cytotoxic soluble aggregates that eventually oligomerize to form fibrils. 140 The characteristic proteins (AD: tau, HD: huntingtin protein (HTT), PD: α-synuclein) are universally substrates of Hsp90. To prevent these proteins from aggregating, they must be ubiquitylated and degraded by the proteosome.…”

Section: Hsp70s and Diseasementioning

confidence: 99%

Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

Ambrose

Chapman

2021

J. Med. Chem.

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Hsp70s are among the most highly conserved proteins in all of biology. Through an iterative binding and release of exposed hydrophobic residues on client proteins, Hsp70s can prevent aggregation and promote folding to the native state of their client proteins. The human proteome contains eight canonical Hsp70s. Because Hsp70s are relatively promiscuous they play a role in folding a large proportion of the proteome. Hsp70s are implicated in disease through their ability to regulate protein homeostasis. In recent years, researchers have attempted to develop selective inhibitors of Hsp70 isoforms to better understand the role of individual isoforms in biology and as potential therapeutics. Selective inhibitors have come from rational design, forced localization, and serendipity, but the development of completely selective inhibitors remains elusive. In the present review, we discuss the Hsp70 structure and function, the known Hsp70 client proteins, the role of Hsp70s in disease, and current efforts to discover Hsp70 modulators.

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Section: Hsp70s and Diseasementioning

confidence: 99%

Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

Ambrose

Chapman

2021

J. Med. Chem.

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“…Protein aggregation formed under certain circumstances has been widely found in many neurodegenerative diseases [ 139 ]. The high throughput character of distance analysis of smFRET empowered screening on aggregation-prone structures and conditions of proteins [ 140 ].…”

Section: Tracking the Interactions Between Biomoleculesmentioning

confidence: 99%

Single-Molecular Förster Resonance Energy Transfer Measurement on Structures and Interactions of Biomolecules

et al. 2021

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Single-molecule Förster resonance energy transfer (smFRET) inherits the strategy of measurement from the effective “spectroscopic ruler” FRET and can be utilized to observe molecular behaviors with relatively high throughput at nanometer scale. The simplicity in principle and configuration of smFRET make it easy to apply and couple with other technologies to comprehensively understand single-molecule dynamics in various application scenarios. Despite its widespread application, smFRET is continuously developing and novel studies based on the advanced platforms have been done. Here, we summarize some representative examples of smFRET research of recent years to exhibit the versatility and note typical strategies to further improve the performance of smFRET measurement on different biomolecules.

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“…Specifically, we will focus on atomic force microscopy (AFM) and single-molecule fluorescence (SMF), particularly single-molecule Förster resonance energy transfer (smFRET). For information outside of the scope of this Review, we refer the reader to a number of in-depth articles on SMF/smFRET and its broad utility in studying disordered proteins. − …”

Section: Amyloids In a Test Tube: Biophysical Characterizations Of Th...mentioning

confidence: 99%

Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments

Gomes

Levine

2021

J. Phys. Chem. B

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The loss of proteostasis over the life course is associated with a wide range of debilitating degenerative diseases and is a central hallmark of human aging. When left unchecked, proteins that are intrinsically disordered can pathologically aggregate into highly ordered fibrils, plaques, and tangles (termed amyloids), which are associated with countless disorders such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, cancer, and even certain viral infections. However, despite significant advances in protein folding and solution biophysics techniques, determining the molecular cause of these conditions in humans has remained elusive. This has been due, in part, to recent discoveries showing that soluble protein oligomers, not insoluble fibrils or plaques, drive the majority of pathological processes. This has subsequently led researchers to focus instead on heterogeneous and often promiscuous protein oligomers. Unfortunately, significant gaps remain in how to prepare, model, experimentally corroborate, and extract amyloid oligomers relevant to human disease in a systematic manner. This Review will report on each of these techniques and their successes and shortcomings in an attempt to standardize comparisons between protein oligomers across disciplines, especially in the context of neurodegeneration. By standardizing multiple techniques and identifying their common overlap, a clearer picture of the soluble neuropathological aggresome can be constructed and used as a baseline for studying human disease and aging.

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Untangling the Conformational Polymorphism of Disordered Proteins Associated With Neurodegeneration at the Single-Molecule Level

Cited by 11 publications

References 121 publications

Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

Single-Molecular Förster Resonance Energy Transfer Measurement on Structures and Interactions of Biomolecules

Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments

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