Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

Abstract

Amyloid beta (Aβ) peptides are a major contributor to Alzheimer's disease. Previously, our group proposed molecular models of Aβ42 hexamers with two concentric antiparallel β-barrels that act as seeds from which dodecamers, octadecamers, both smooth and beaded annular protofibrils, and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Here we develop a more extensive range of models to be consistent with dimensions of assemblies observed in electron microscopy images of annular protofibrils and transmembrane assemblies. These models have the following features: Dodecamers with 2-concentric β-barrels are the major components of beaded annular protofibrils (bAPFs). These beads merge to form smooth annular protofibrils (sAPFs) that have three or four concentric β-barrels. Channels form from two to nine hexamers. Antiparallel C-terminus S3 segments form an outer transmembrane β-barrel. Half of the monomers of vertically asymmetric 12mer to 36mer channels form parallel transmembrane S2 β-barrels, and S1-S2 (N-terminus and middle) segments of the other half of the monomers form aqueous domains on the cis side of the membrane. Unit cells of 42-54mers have two more transmembrane S2 segments, with four concentric β-barrels in the transmembrane region and two concentric β-barrels on the cis side of the membrane.

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

“…Values of these parameter are limited by symmetry constraints and depend upon the number of strands/monomer in a α barrel. S/N values of the models presented here are consistent with those that have been commonaly observed; they range from 0.4 to 1.5 with the most common being 1.0 (see Table S1 of the supplement and detailed description of theory in Durell et al [30]). The structures are even more constrained if the assembly has concentric β-barrels because all of the barrels must have the same axes of symmetry.…”

“…We utilize an alternative approach to modeling oligomers and transmembrane channels that concentrates on β-barrels, most of which are concentric. Previously we published concentric β-barrel models of amyloid-β42 (Aβ42) hexamers, dodecamers, annular protofibrils, and transmembrane channels [28–30]. Several aspects of our models including six-stranded antiparallel β-barrels and concentric β-barrels were unprecedented.…”

“…Stimulated by these and other supportive experimental findings, we have renewed our modeling efforts. Although some details of our current generation of models have been altered and are still evolving, the basic concept of assemblies composed of concentric β-barrels [30] has been retained. Here we extend those concepts and techniques to develop models of a variety of non-fibril Synuclein assemblies.…”

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

“…The process of fibrillogenesis begins with amyloid monomers that assemble to form dimers and small oligomer species, followed by aggregation of oligomers to further construct short, irregular protofibrils and elongate into insoluble fibrils via a complex multistep-nucleated polymerization (Cheignon et al, 2018). Once Aβ aggregates extracellularly to form fibrils, it becomes resistant to proteolytic cleavage (Durell et al, 2018). Our strategy was to either inhibit or disaggregate the fibril formation process to prevent amyloidogenesis by using optimized concentrations of singular and combined compounds.…”

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

“…The head-to-tail aggregation of extended conformers of such antiparallel dimers and tetramers is assumed to yield oligomers which by a combination of twist, bend and rise can fold into “jelly-roll”-like cylindrical structures and subsequently into β barrels. Depending on the extension of its core, the initial barrel may convert into a concentric β barrel (Shafrir et al, 2010; Durell et al, 2018); while no such structures were actually isolated, this pathway seems to be consistent with a wide range of indirect evidence (Durell et al, 2018). (C) Formation of the parallel cross-β structures: The head-to-tail aggregation of coiled-coil conformers of the antiparallel dimers is assumed to yield circular wedge-shaped paranuclei (Fu et al, 2015; Economou et al, 2016); higher-order annular aggregates of such paranuclei are then expected to undergo conformational antiparallel-to-parallel β structure conversion to yield fibrils which assemble two protofilaments comprising parallel cross-β sheets and aligned in the antiparallel fashion (Schmidt et al, 2015).…”