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 EM 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.