The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Abstract

Amyloid beta (Aβ of Alzheimer's disease) and α-synuclein (α-Syn of Parkinson's disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by electron microscopy and other studies.The models have the following features: (1) all subunits have identical structures and interactions; (2) they are consistent with conventional β-barrel theory; (3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; (4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and (5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

“…The first was on synucleins, especially α-synuclein associated with Parkinson's disease. 45 Others in progress involve Aβ42 channels, amylin (or islet amyloid polypeptide) assemblies, and interactions of various amyloids (synucleins, amylin, humanin, and human cystatin C) with Aβ42 hexamers. These papers are follow-ups to and an expansion of our earlier publications on concentric β-barrel models of Aβ42 oligomers, APFs, and ion channels, 21,22 utilizing recent experimental results and image averaging.…”

“…This is the second paper of a series on the concentric β‐barrel hypothesis for nonfibril amyloid assemblies. The first was on synucleins, especially α‐synuclein associated with Parkinson's disease 45 . Others in progress involve Aβ42 channels, amylin (or islet amyloid polypeptide) assemblies, and interactions of various amyloids (synucleins, amylin, humanin, and human cystatin C) with Aβ42 hexamers.…”

“…This feature constrains symmetric models with concentric β‐barrels because all barrels must have the same axes of symmetry. The gap distance between the walls of the adjacent barrels were constrained to be between 0.6 and 1.2 nm, 45 depending primarily on the side chain sizes. We favor models in which interacting pleats of adjacent β‐barrels fit between each other in a manner that reduces clashes among side chains, and in which all pleats that intersect the axes of twofold symmetry have the same inward or outward side‐chain orientation in all concentric β‐barrels.…”

“…We favor models in which interacting pleats of adjacent β‐barrels fit between each other in a manner that reduces clashes among side chains, and in which all pleats that intersect the axes of twofold symmetry have the same inward or outward side‐chain orientation in all concentric β‐barrels. We call this type of interaction “Intermeshing Pleats.” 45 We selected models that maximize hydrogen bonds, salt bridges, interactions among aromatic side chains, burial and tight packing of hydrophobic side chains that are highly conserved among Aβ homologs, and aqueous solvent exposure of hydrophilic side chains, especially for positions that are hypervariable among homologs. Residues with polar side chains and/or that have a high propensity for turn or coil secondary structure 27 and that contain proline in some homologs were favored for connecting loops.…”

“…As pointed out in our paper on models of synuclein assemblies, 45 our hypothetical models are likely overstructured. They do not adequately capture the dynamic nature of amyloid assemblies in which the number of monomers, how they interact, and even secondary structures appear to transition among numerous alternatives.…”