Impact of membrane curvature on amyloid aggregation

Abstract

The misfolding, amyloid aggregation, and fibril formation of intrinsically disordered proteins/peptides (or amyloid proteins) have been shown to cause a number of disorders. The underlying mechanisms of amyloid fibrillation and structural properties of amyloidogenic precursors, intermediates, and amyloid fibrils have been elucidated in detail; however, in-depth examinations on physiologically relevant contributing factors that induce amyloidogenesis and lead to cell death remain challenging. A large number of studies have attempted to characterize the roles of biomembranes on protein aggregation and membrane-mediated cell death by designing various membrane components, such as gangliosides, cholesterol, and other lipid compositions, and by using various membrane mimetics, including liposomes, bicelles, and different types of lipid-nanodiscs. We herein review the dynamic effects of membrane curvature on amyloid generation and the inhibition of amyloidogenic proteins and peptides, and also discuss how amyloid formation affects membrane curvature and integrity, which are key for understanding relationships with cell death. Small unilamellar vesicles with high curvature and large unilamellar vesicles with low curvature have been demonstrated to exhibit different capabilities to induce the nucleation, amyloid formation, and inhibition of amyloid-β peptides and α-synuclein. Polymorphic amyloidogenesis in small unilamellar vesicles was revealed and may be viewed as one of the generic properties of interprotein interaction-dominated amyloid formation. Several mechanical models and phase diagrams are comprehensively shown to better explain experimental findings. The negative membrane curvature-mediated mechanisms responsible for the toxicity of pancreatic β cells by the amyloid aggregation of human islet amyloid polypeptide (IAPP) and binding of the precursors of the semen-derived enhancer of viral infection (SEVI) are also described. The curvature-dependent binding modes of several types of islet amyloid polypeptides with high-resolution NMR structures are also discussed.

β‐Amyloid aggregation and heterogeneous nucleation

“…Reprinted from Reference 35 the fibrillar products depend not only on lipid composition but also on physical factors such as radius of curvature of the surface. [68][69][70] In line with the above studies, it has been shown that the effects of membranes on Aβ aggregation are modulated by variations in membrane fluidity. The main regulator of mammalian membrane fluidity is cholesterol.…”

“…With large unilamellar vesicles, however, low POPC concentrations did not affect fibrillization kinetics markedly, but at higher POPC concentration, this lipid suppressed fibril formation. Thus, aggregation kinetics and the structure of the fibrillar products depend not only on lipid composition but also on physical factors such as radius of curvature of the surface …”

Membrane interactions accelerate the self-aggregation of huntingtin exon 1 fragments in a polyglutamine length-dependent manner

“…Thereby these and other biophysical observations provide a rationale for a number of biochemical and cell biological experiments where huntingtin has been shown associated with membranes of intracellular organelles (6,10,13,(16)(17)(18)(19)(20)25) or where the membrane anchoring domain htt17 has been demonstrated to promote the development of the disease (6,13,26,30,(36)(37)(38). Such lipid interactions have been shown to be modulators of aggregation and fibril formation also for α -synuclein (57,62,64), islet amyloid polypeptide (9) and βamyloid (58,84). Within these studies the detailed membrane composition including the resulting physico-chemical properties such as negative charge density, fluidity, saturation, curvature or interactions with specific lipids all play important roles in the aggregation process (9,39,56,76,85).…”

“…It has been suggested that polyglutamines perturb neuronal membranes, result in their disruption concomitant with calcium dysregulation (6, 7) thereby causing Huntington's or other amyloidogenic diseases (8)(9)(10). Huntingtin or fragments of the protein have been shown to be involved in intracellular vesicle trafficking (10)(11)(12).…”

“…Furthermore, membranes could alter aggregate morphology to specific toxic species or stabilize potentially toxic, transient aggregation intermediates (8,(59)(60)(61). Therefore, investigations of how amyloid fibrils as well as their intermediate and protofibrillar…”