Biophysical Society Conference | Estes Park 2023

Membrane Budding and Fusion

Poster Abstracts

32-POS Board 11 CONCENTRIC BETA-BARREL MODELS OF OLIGOMERS, PROTOFIBRILS, AND MEMBRANE CHANNELS FORMED BY AMYLOID BETA (ALZHEIMER'S DISEASE), SYNUCLEINS (PARKINSON'S DISEASED), AND AMYLIN (TYPE 2 DIABETES)

H. R Guy 1 ; H. Robert Guy 1 ; 1 Amyloid Research Consultants (ARC), Cochiti Lake, NM, USA

Amyloid- forming peptides and proteins underlie or are involved in Alzheimer’s (Amyloid β or Aβ), Parkinson’s (α - Synuclein or α -Syn), Type 2 diabetes (Amylin or IAPP). These diseases kill millions and cost about a trillion dollars annually. Some variants of each of these peptides form ion channels in membranes that experience exocytosis and endocytosis at synapses and pancreatic islets and fusion, fission, and swelling in mitochondria. However; little is known about exactly how they act and which assemblies are functional and which are pathogenic. I and my colleagues have been developing structural models of Aβ channels for almost three decades. We have now revised and expanded our Aβ42 models and have extended the hypothesis of concentric β -barrel amyloid as semblies to α - Syn and Amylin (IAPP). Our current models of Aβ include interactions with GM1 gangliosides and cholesterol and interactions of the three types of amyloids with each other. Symmetric β -barrels often have well defined structures composed of mul tiple subunits with identical conformations. Well established β -barrel theory can be used to model these structures accurately if one is able to determine the number of subunits per barrel, the number of strands per subunit, which segments comprise the β -strands, and dimensions of the barrel. Most of our models of numerous oligomers, annular protofibrils, lipoprotein complexes, and transmembrane channels contain symmetric β -barrels with radial and P2 two-fold symmetry. These models are consistent with molecular modeling principles and biochemical and biophysical data, including microscopic images, cryoEM, and NMR results. Hypothetical models and concepts are vital for research because they often suggest experiments that otherwise would not be performed or funded. Our models suggest experiments to test aspects of the models, to reduce polymorphism and disorder so that specific structures can be solved experimentally, and to identify specific segments to target for drug and antibody treatments.

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