Disordered Proteins: Biological Membranes as Two-Dimensional Aggregation Matrices

Abstract

Aberrant folded proteins and peptides are hallmarks of amyloidogenic diseases. However, the molecular processes that cause these proteins to adopt non-native structures in vivo and become cytotoxic are still largely unknown, despite intense efforts to establish a general molecular description of their behavior. Clearly, the fate of these proteins is ultimately linked to their immediate biochemical environment in vivo. In this review, we focus on the role of biological membranes, reactive interfaces that not only affect the conformational stability of amyloidogenic proteins, but also their aggregation rates and, probably, their toxicity. We first provide an overview of recent work, starting with findings regarding the amphiphatic amyloid-beta protein (Abeta), which give evidence that membranes can directly promote aggregation, and that the effectiveness in this process can be related to the presence of specific neuronal ganglioside lipids. In addition, we discuss the implications of recent research (medin as an detailed example) regarding putative roles of membranes in the misfolding behavior of soluble, non-amphiphatic proteins, which are attracting increasing interest. The potential role of membranes in exerting the toxic action of misfolded proteins will also be highlighted in a molecular context. In this review, we discuss novel NMR-based approaches for exploring membrane-protein interactions, and findings obtained using them, which we use to develop a molecular concept to describe membrane-mediated protein misfolding as a quasi-two-dimensional process rather than a three-dimensional event in a biochemical environment. The aim of the review is to provide researchers with a general understanding of the involvement of membranes in folding/misfolding processes in vivo, which might be quite universal and important for future research concerning amyloidogenic and misfolding proteins, and possible ways to prevent their toxic actions.

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

“…2 by Uversky in this volume). Moreover, "molecular crowding", which results from the local increase in peptide concentrations upon adsorption to a 2D surface, as well as the local decrease in pH at the membrane surface, are also expected to promote intermolecular β-sheet formation and Aβ aggregation (Bokvist and Groebner 2007 ;Bystroem et al 2008 ). Together, these effects can induce a specifi c misfolding pathway in Aβ, generating toxic aggregates Bystroem et al 2008 ).…”

DHPC Strongly Affects the Structure and Oligomerization Propensity of Alzheimer's Aβ(1–40) Peptide

“…22,23 In addition, lipids can influence the Aβ aggregation and fibrillation behaviour. [24][25][26] For example, PEGylated phospholipid micelles attenuate the formation of β-sheet structure and Aβ neurotoxicity in vitro, 20 while phosphatidylglycerol, but not phosphatidylcholine, vesicles trigger the formation of β-sheet structure. 16,17 Similar β-sheetinducing effects were reported for dodecyl phosphatidylcholine 21 and sub-CMC (critical micelle concentrations) of sodium dodecyl sulfate (SDS).…”

Wavy membranes and the growth rate of a planar chemical garden: Enhanced diffusion and bioenergetics

“…Reactive interfaces play in general an important role in many chemical (11,12), biological, and engineering processes in instances ranging from heterogeneous catalysis (13) to protein activity in biological membranes (14,15) and to environmental flows (16). For liquid-liquid interfaces, most chemical research focuses on immiscible liquids such as certain polymer melts (17,18) and emulsions because sharp interfaces between miscible liquids are difficult to generate and swiftly decay owing to diffusion and other transport phenomena.…”