Structure and Aggregation Mechanisms in Amyloids

Abstract

The aggregation of a polypeptide chain into amyloid fibrils and their accumulation and deposition into insoluble plaques and intracellular inclusions is the hallmark of several misfolding diseases known as amyloidoses. Alzheimer's, Parkinson's and Huntington's diseases are some of the approximately 50 amyloid diseases described to date. The identification and characterization of the molecular species critical for amyloid formation and disease development have been the focus of intense scrutiny. Methods such as X-ray and electron diffraction, solid-state nuclear magnetic resonance spectroscopy (ssNMR) and cryo-electron microscopy (cryo-EM) have been extensively used and they have contributed to shed a new light onto the structure of amyloid, revealing a multiplicity of polymorphic structures that generally fit the cross-β amyloid motif. The development of rational therapeutic approaches against these debilitating and increasingly frequent misfolding diseases requires a thorough understanding of the molecular mechanisms underlying the amyloid cascade. Here, we review the current knowledge on amyloid fibril formation for several proteins and peptides from a kinetic and thermodynamic point of view, the structure of the molecular species involved in the amyloidogenic process, and the origin of their cytotoxicity.

Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X

“…The protein concentration spanned from 7.5 μM to 60 μM. ThT fluorescence recorded during this process displayed sigmoid-shaped curves, typical of the nucleation-elongation mechanism of fibrillation, in which fibrils are assembled through the sequential addition of monomers to a nucleus ( Figure S6 C) ( Almeida and Brito, 2020 ; Librizzi and Rischel, 2005 ). As a first guide to determine the dominant fibril assembly mechanism, we investigated the half-time (t 1/2 ) dependence on initial protein concentration (C 0 ).…”

Diverse Aggregation Kinetics Predicted by a Coarse-Grained Peptide Model

“… 3 Despite intense experimental and theoretical work, peptide aggregation is not yet completely understood. 4 , 5 An important issue in peptide aggregation is the molecular mechanism of aggregate nucleation and growth. In many experimental studies, sigmoidal kinetics curves show a clear lag phase ascribed to nucleation, where the initially formed small oligomers equilibrate with free monomers until aggregates of the critical size are formed.…”

“…In many experimental studies, sigmoidal kinetics curves show a clear lag phase ascribed to nucleation, where the initially formed small oligomers equilibrate with free monomers until aggregates of the critical size are formed. 5 However, experimental studies also show downhill kinetics curves, where the monomers decay continuously and no lag phase can be seen. Examples of downhill aggregation include the SH3 domain of α-spectrin (Spc-SH3), 6 transthyretin (TTR), 7 , 8 human serum albumin (HSA), 9 bovine serum albumin (BSA), and α-chymotrypsinogen A (α-chymo).…”

Exploring ensemble structures of Alzheimer’s amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift

“…Heterogeneous and transient initial structures and intermolecular interactions of disordered precursors in ensembles significantly hamper accurate and precise investigations on the early event of amyloid formation and the oligomerization. In order to overcome these difficulties, various in silico approaches including the molecular dynamics (MD) simulation and theoretical computation have been efficiently developed and exploited, which provided invaluable insights into the possible structural state and molecular association of amyloid proteins for aggregation [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] .…”