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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-? 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.

SUBMITTER: L Almeida Z

PROVIDER: S-EPMC7179426 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Structure and Aggregation Mechanisms in Amyloids.

Almeida Zaida L ZL Brito Rui M M RMM

Molecules (Basel, Switzerland) 20200306 5

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. ...[more]

PMID: 32155822

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Project description:The amyloid structures and their wild type forms, available in the PDB database, provide the basis for comparative analyses. Globular proteins are characterised by a 3D spatial structure, while a chain in any amyloid fibril has a 2D structure. Another difference lies in the structuring of the hydrogen bond network. Amyloid forms theoretically engage all the NH and C=O groups of the peptide bonds in a chain with two hydrogen bonds each. In addition, the hydrogen bond network is highly ordered-as perpendicular to the plane of the chain. The β-structure segments provide the hydrogen bond system with an anti-parallel system. The folds appearing in the rectilinear propagation of the segment with the β-structure are caused by just by one of the residues in the sequence-residues with a Rα-helical or Lα-helical conformation. The antiparallel system of the hydrogen bonds in the β-structure sections at the site of the amino acid with a Rα- or Lα-helical conformation changes into a parallel system locally. This system also ensures that the involvement of the C=O and H-N groups in the construction of the interchain hydrogen bond, while maintaining a perpendicular orientation towards the plane of the chain. Conformational analysis at the level of the Phi and Psi angles indicates the presence of the conditions for the structures observed in the amyloids. The specificity of amyloid structures with the dominant conformation expressed as |Psi| = |Phi| reveals the system of organisation present in amyloid fibrils. The Phi, Psi angles, as present in this particular structure, transformed to form |Psi| = |Phi| appear to be ordered co-linearly. Therefore, the calculation of the correlation coefficient may express the distribution around this idealised localisation on the Ramachandran map. Additionally, when the outstanding points are eliminated, the part of amyloid chain can be classified as fulfilling the defined conditions. In addition, the presentation of the chain structure using geometric parameters, V-angle-the angle between the planes of the adjacent peptide bonds (angle versus the virtual axis Cα-Cα) and the radius of the curvature R, depending on the size of the angle V, allows for a quantitative assessment of changes during amyloid transformation.

Dataset Information

Structure and Aggregation Mechanisms in Amyloids.

Publications

Structure and Aggregation Mechanisms in Amyloids.

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