Using mass spectrometry-based methods to understand amyloid formation and inhibition of alpha-synuclein and amyloid beta.

Autor: Wagner WJ; Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri, USA., Gross ML; Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri, USA.
Jazyk: angličtina
Zdroj: Mass spectrometry reviews [Mass Spectrom Rev] 2024 Jul-Aug; Vol. 43 (4), pp. 782-825. Date of Electronic Publication: 2022 Oct 12.
DOI: 10.1002/mas.21814
Abstrakt: Amyloid fibrils, insoluble β-sheets structures that arise from protein misfolding, are associated with several neurodegenerative disorders. Many small molecules have been investigated to prevent amyloid fibrils from forming; however, there are currently no therapeutics to combat these diseases. Mass spectrometry (MS) is proving to be effective for studying the high order structure (HOS) of aggregating proteins and for determining structural changes accompanying protein-inhibitor interactions. When combined with native MS (nMS), gas-phase ion mobility, protein footprinting, and chemical cross-linking, MS can afford regional and sometimes amino acid spatial resolution of the aggregating protein. The spatial resolution is greater than typical low-resolution spectroscopic, calorimetric, and the traditional ThT fluorescence methods used in amyloid research today. High-resolution approaches can struggle when investigating protein aggregation, as the proteins exist as complex oligomeric mixtures of many sizes and several conformations or polymorphs. Thus, MS is positioned to complement both high- and low-resolution approaches to studying amyloid fibril formation and protein-inhibitor interactions. This review covers basics in MS paired with ion mobility, continuous hydrogen-deuterium exchange (continuous HDX), pulsed hydrogen-deuterium exchange (pulsed HDX), fast photochemical oxidation of proteins (FPOP) and other irreversible labeling methods, and chemical cross-linking. We then review the applications of these approaches to studying amyloid-prone proteins with a focus on amyloid beta and alpha-synuclein. Another focus is the determination of protein-inhibitor interactions. The expectation is that MS will bring new insights to amyloid formation and thereby play an important role to prevent their formation.
(© 2022 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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