Interactions of Lipid Membranes with Fibrillar Protein Aggregates

Abstract

Amyloid fibrils are an intriguing class of protein aggregates with distinct physicochemical, structural and morphological properties. They display peculiar membrane-binding behavior, thus adding complexity to the problem of protein-lipid interactions. The consensus that emerged during the past decade is that amyloid cytotoxicity arises from a continuum of cross-β-sheet assemblies including mature fibrils. Based on literature survey and our own data, in this chapter we address several aspects of fibril-lipid interactions, including (i) the effects of amyloid assemblies on molecular organization of lipid bilayer; (ii) competition between fibrillar and monomeric membrane-associating proteins for binding to the lipid surface; and (iii) the effects of lipids on the structural morphology of fibrillar aggregates. To illustrate some of the processes occurring in fibril-lipid systems, we present and analyze fluorescence data reporting on lipid bilayer interactions with fibrillar lysozyme and with the N-terminal 83-residue fragment of amyloidogenic mutant apolipoprotein A-I, 1-83/G26R/W@8. The results help understand possible mechanisms of interaction and mutual remodeling of amyloid fibers and lipid membranes, which may contribute to amyloid cytotoxicity.

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes

“…In contrast to these results, the use of gap junction inhibitors (CBX, MQ and 2-APB) successfully blocked soluble and insoluble (fibrillar) α-syn uptake in both neurons and oligodendrocytes. The lack of fibrillar uptake inhibition by peptide mimetics may in part be explained by the high affinity of fibrillar α-syn assemblies to cellular membranes [ 18 ], the selective binding of Cx32 to oα-syn, the limited efficacy of the Cx32 peptide sequences used (which may not target the region interest) and/or the half-life of the peptides within the cells. However, other mechanisms cannot be ruled out including an unidentified Cx that may be involved in the preferential uptake of fibrillar α-syn assemblies.…”

The association of lipids with amyloid fibrils

“…This nucleation may happen when the monomer is associated with a membrane or in free solution and occurs during the lag phase of fibrillogenesis. It is a fundamental point that there are multiple pathways for fibril formation, many of which lead to fibrils with differing structural and morphological properties ( 14 , 18 , 26 , 27 ). The biologically relevant morphology may be different from one produced from a purified protein in vitro under a given set of conditions.…”

“…The biologically relevant morphology may be different from one produced from a purified protein in vitro under a given set of conditions. In many cases, it has been demonstrated that fibril formation is promoted following membrane binding of a protein monomer or a protein oligomer ( 14 , 28 , 29 , 30 , 31 , 32 ). This acceleration is generally attributed to a combination of factors, including the bound protein adopting a more favorable conformation for nucleation, the concentration of the protein into a small volume, and changing the process from one occurring in bulk solution to one that is effectively a 2-dimensional process ( 28 ).…”

“…The focus subsequently shifted to address protein aggregation. In recent years however, in the face of a wealth of data on peptide and protein assembly into fibrils, it has become apparent that membranes have a key role in accelerating assembly in vivo and driving assembling intermediates into conformations that are on-pathway for fibril formation ( 8 , 9 , 10 , 11 , 12 , 13 , 14 ). But whilst assembly processes have been well characterized under controlled conditions in vitro , a number of significant challenges remain in understanding both the processes that occur in vivo that lead to otherwise normal functioning peptides and proteins becoming directed down aberrant folding pathways and the parts of this process where cellular damage occurs.…”

“…A particularly complex challenge is understanding the link between fibrillogenesis and biological outcomes, as it is frequently difficult to relate the in vitro behavior to the in vivo toxicity. Fibrils formed in the presence of lipids, for example, can exhibit differing morphologies according to the method of preparation ( 11 , 14 , 15 , 16 , 17 ). For many diseases that involve the formation of amyloid fibrils, the precise physiological circumstances that trigger toxic fibril formation are still poorly characterized, and a number of phenomena lack detailed information at the molecular level, such as how changes in lipid composition are able to influence nucleation kinetics and fibril morphology ( 18 , 19 ).…”