The role of α-sheet structure in amyloidogenesis: characterization and implications

Abstract

Amyloid diseases are linked to protein misfolding whereby the amyloidogenic protein undergoes a conformational change, aggregates and eventually forms amyloid fibrils. While the amyloid fibrils and plaques are hallmarks of these diseases, they typically form late in the disease process and do not correlate with disease. Instead, there is growing evidence that smaller, soluble toxic oligomers form prior and appear to be early triggers of the molecular pathology underlying these diseases. Nearly 20 years ago, we proposed the α-sheet hypothesis after discovering that the early conformational changes observed during atomistic molecular dynamics simulations involve the formation of a non-standard protein structure, α-sheet. Furthermore, we proposed that toxic oligomers contain α-sheet structure and that preferentially targeting this structure could neutralize the toxicity, prevent further aggregation and serve as the basis for early detection of disease. Here, we present the origin of the α-sheet hypothesis and describe α-sheet structure and the corresponding mechanisms of conversion. We discuss experimental studies demonstrating that both mammalian and bacterial amyloid systems form α-sheet oligomers before converting to conventional β-sheet fibrils. Furthermore, we show that the process can be inhibited with de novo designed α-sheet peptides complementary to the structure in the toxic oligomers.

Cytotoxic Staphylococcus aureus PSMα3 inhibits the aggregation of human insulin in vitro

“…21 In our case, we also demonstrated that PSMa3 maintains a-helical conformation up to several days of incubation at 37 1C, wherein a-helical-designed peptides were shown before to suppress amyloid aggregation with high efficiency, including both bacterial and mammalian peptides and proteins. [64][65][66][67] This is probably determined by the fact that the formation of intermediate cross-a-sheet-like structures is a universally adopted amyloidogenic motif during the amyloid selfassembly process, which has been shown to be associated with high toxicity and demonstrated before for the different pathogenic amyloids, such as Ab, a-syn, transferrin, amylin, and others. 64,[68][69][70][71] In particular, these kinds of transient oligomer species, composed primarily of a-sheets, were also described before for human insulin.…”

“…[64][65][66][67] This is probably determined by the fact that the formation of intermediate cross-a-sheet-like structures is a universally adopted amyloidogenic motif during the amyloid selfassembly process, which has been shown to be associated with high toxicity and demonstrated before for the different pathogenic amyloids, such as Ab, a-syn, transferrin, amylin, and others. 64,[68][69][70][71] In particular, these kinds of transient oligomer species, composed primarily of a-sheets, were also described before for human insulin. 72 It was also recently demonstrated that the mechanism of inhibition of insulin fibrillation by short ahelical peptides is based on hydrogen bond formation with amino acid residues in both insulin chains that interfere with the insulin conformational transition from a-helix to b-sheet.…”

Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy

“…The proposal had previously been made (recently [ 23 , 24 , 25 ]) that AD is caused by a toxic protein conformation called α-sheet, a protein conformation discovered by Pauling and Corey [ 26 , 27 ] before they discovered the well-known β-sheet. Molecular dynamics simulation has shown that α-sheets and β-sheets can interconvert [ 25 , 28 , 29 ], with interconversion stimulated by side-chain hydrophilicity [ 25 ].…”

“…The proposal had previously been made (recently [ 23 , 24 , 25 ]) that AD is caused by a toxic protein conformation called α-sheet, a protein conformation discovered by Pauling and Corey [ 26 , 27 ] before they discovered the well-known β-sheet. Molecular dynamics simulation has shown that α-sheets and β-sheets can interconvert [ 25 , 28 , 29 ], with interconversion stimulated by side-chain hydrophilicity [ 25 ]. The α-sheet-as-disease-causing-agent proposal is dramatically supported by the observation that the toxic form of in vitro-assembled AD amyloid proteins (cleaved Aβ protein, 40–42 amino acids long; review [ 28 , 29 ]) have two characteristics of α-sheets: (1) circular dichroism near zero and (2) an appropriate NMR signature [ 23 , 24 , 25 ].…”

Human islet amyloid polypeptide‐induced β‐cell cytotoxicity is linked to formation of α‐sheet structure

“…α-Sheet is defined by the alignment of the amide groups on one side of the backbone and the carbonyl groups on the other (Daggett, 2006). We designed nontoxic, stable α-sheet peptides complementary to the presumed α-sheet structure in the toxic oligomers (Bleem et al, 2017;Bleem et al, 2023;Daggett, 2006;Hopping et al, 2014;Kellock et al, 2016;Maris et al, 2018;Prosswimmer & Daggett, 2022;Shea et al, 2019). We reasoned that these α-sheet peptides would neutralize toxicity and inhibit fibril formation by specifically binding to toxic oligomers.…”