Biology subjects

Durell, S. R.

Publications and source records attributed to Durell, S. R..

3 recordsLinked to original sources

bioRxiv2026

The concentric beta-barrel hypothesis for amyloids: Models of soluble and transmembrane amyloid-beta 42 oligomers and channels composed of identical subunits and GM1 gangliosides.

Soluble oligomers and transmembrane channels formed by the 42-residue variant of amyloid beta (A{beta}42) play key roles in Alzheimers disease. Unfortunately, detailed structures of these assemblies have not been determined. Our group addresses this problem by developing atomic scale models. Previously we proposed that both soluble A{beta}42 oligomers and transmembrane channels have symmetric concentric {beta}-barrel structures. Here we expand this hypothesis to include GM1 gangliosides and sometimes cholesterol and lattice models of channel assemblies. The presence of GM1 gangliosides increases the toxicity of A{beta}42, enhances its ability to penetrate liposome membranes, and facilitates interactions between adjacent liposomes. Although the conformations of numerous model assemblies vary, in these models the carboxyl group of GM1 always binds to side-chains of histidine 13 and/or histidine 14. Our soluble oligomer models are consistent with electron microscopy images of beaded annular protofibrils. Our models of membrane-bound assemblies are consistent with the following: freeze-fracture and atomic force microscopy images of A{beta}42 in lipid bilayers, secondary structure results, the calcium hypothesis of Alzheimers Disease, effects of lithium depletion on AD, established {beta}-barrel theory, and energetic criteria.

neuroscience↗

bioRxiv2021

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

Amyloid beta (A{beta}) peptides, a major contributor to Alzheimers disease, occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by A{beta}42; some of which have antiparallel {beta}-sheets. Previously, our group proposed molecular models of A{beta}42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded {beta}-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to 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. Recently, NMR-based structures have been proposed for A{beta}42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~ 32 monomers. Here we propose a range of concentric {beta}-barrel models and compare their dimensions to image-averaged electron micrographs of both beaded annular protofibrils (bAPFs) and smooth annular protofibrils (sAPFs) of A{beta}42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These gradually morph into sAPFs in which a S3 {beta}-barrel is shielded on one or both sides by {beta}-barrels formed from S1 and S2 segments.

biophysics↗

bioRxiv2018

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

Amyloid beta (A{beta}) peptides are a major contributor to Alzheimers disease. Previously, our group proposed molecular models of A{beta}42 hexamers with two concentric antiparallel {beta}-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 {beta}-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 {beta}-barrels. Channels form from two to nine hexamers. Antiparallel C-terminus S3 segments form an outer transmembrane {beta}-barrel. Half of the monomers of vertically asymmetric 12mer to 36mer channels form parallel transmembrane S2 {beta}-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 {beta}-barrels in the transmembrane region and two concentric {beta}-barrels on the cis side of the membrane.

neuroscience↗