The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes.
The dynamics, energies, and structures governing protein folding are critical to biological function. Amyloidoses are a class of disease defined, in part, by the misfolding and aggregation of functional protein precursors into fibrillar states. Amyloid fibers contribute to the pathology of many diseases, including type II diabetes, Alzheimer's, and Parkinson's. In these disorders, amyloid fibers are present in affected tissues. However, it has become clear that intermediate states, rather than mature fibers, represent the cytotoxic species. In this review, we focus particularly on lipid bilayer-bound intermediates. Remarkably, the precursors of these fibers are intrinsically disordered, and yet catalysis of beta-sheet formation appears to be mediated by the stabilization of alpha-helical states. On the lipid bilayer, these intermediate species have been implicated as cytotoxic through elimination of ionic homeostasis. Recent advances are enabling insights at a molecular level that promise to provide meaningful targets for the development of therapeutics.
Hebda
James A
JA
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
Miranker
Andrew D
AD
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002384:Catalysis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers