Probing the interplay between amyloidogenic proteins and membranes using lipid monolayers and bilayers
Graphical abstract
Introduction
Several clinical syndromes, described as amyloid diseases, including Alzheimer's and Parkinson's, are caused by the aggregation of specific proteins and peptides. Amyloidogenic proteins or peptides of different amino acid compositions share a tendency to aggregate in a similar way. These similarities provide support for the hypothesis that amyloid aggregate interaction with membranes and/or receptors can be associated with a shared basic form of the aggregates rather than with the type of protein or peptide that forms the aggregates, as reviewed in [1]. Amyloidogenic proteins show similar pathways of fibrillization, including the formation of prefibrillar oligomers characterized by globular structures typically of few nanometers. These oligomers evolve into linear or annular structures, which then form insoluble fibrillar aggregates (Fig. 1). Amyloid fibrils (Fig. 2) have lengths in the micron range, diameters in the nanometer range, and, in tissues, they form clusters easily observed by optical microscopy after staining. This assembly of proteins or peptides into mature amyloid fibrils is a multistep process typical of a nucleation–polymerization pathway. Initially, the process is characterized by a lag phase, during which monomers oligomerize and form aggregation nuclei. These nuclei act as aggregation seeds and elongate into a variety of intermediates eventually evolving into mature fibrils characterized by a cross-β core structure [1], [2]. Following the aggregation kinetics of β2-microglobulin, a protein associated with dialysis-related amyloidosis, Yoshimura et al. showed that, under different experimental conditions, the protein follows two different aggregation pathways: either the formation of crystal-like amyloid fibrils or amorphous aggregates. Comparing the aggregation kinetics they found that only the first pathway is characterized by a sigmoidal profile [3]. Monte Carlo simulations show that a simple model involving molecules with two internal states may account for the sigmoidal profile generally observed in amyloid fibril aggregation [4].
It is generally accepted that in most cases the toxicity of amyloids is related to the existence of various intermediate structures that precede fibril formation and are characterized by a marked polymorphism [5], [6]. For the first time the X-ray derived atomic structure of a small toxic oligomer of αB crystallin has been determined and has been found to consist of six antiparallel beta strands [7]. The structure of Aβ aggregates, the main component of senile plaques in Alzheimer's disease, has been elucidated using a variety of techniques [8], [9], [10]. In addition, it has been shown that the same protein, in different environmental conditions (i.e. pH, temperature, solvent composition, ionic strength), may form aggregates of different toxicities [11], [12] or of different structures [13].
Lipid membranes are known to catalyze the formation of amyloid aggregates and the biophysical properties of the lipids themselves may be of particular importance in determining the properties of the aggregates [14], [15]. Significantly, it has been shown that in pathogenic conditions such as Alzheimer's disease, the composition of phospholipids in the brain is altered [16]. Conversely, disruption of membrane integrity caused by aggregate–membrane interaction results from both protein aggregate and membrane properties.
Despite the intense work in this field, a clear characterization of the amyloid intermediates and of the mechanism of their interaction with membranes is far from complete. In this review we focus on the importance of model systems (monolayers and bilayers) in elucidating the interplay between membrane-catalyzed oligomer formation and oligomer–membrane interactions that cause perturbation and disruption of the typical barrier properties of the cell membrane, eventually leading to cell death.
A lipid monolayer at the air–water interface or a self-assembled monolayer on solid support (SAM) is a basic model of a single membrane leaflet [17]. Therefore, such a simple model system can be employed to study the interactions occurring at the surface of biological membranes, and in particular to probe the interactions with amyloidogenic proteins. Lipid bilayers (BLMs), supported lipid bilayers (sBLMs), and vesicles are well-defined membrane model systems often amenable to molecular scale characterization techniques. By providing a variety of lipid environments they give insight into the modulating effects of membranes on protein aggregation, while measurements of ionic conductance, surface morphology and fluorescence leakage shed light on protein disruptive effects on membranes.
Section snippets
Protein aggregation in a membrane environment: The relevance of interfaces
The study of membrane-assisted fibrillogenesis (Fig. 3) has been inspired by many important questions with medical and physiological relevance, as amyloid aggregates exert their cytotoxic activity at cell membranes rather than in bulk [18]. The most intriguing questions raised in these studies are related to the role of membranes (in particular their lipid composition or the presence of lipid rafts) in determining oligomer formation and to the forces involved in oligomer–surface interactions. A
Monolayer destabilization
Interactions of amyloidogenic proteins with monolayers can result in protein insertion into the monolayer, altering its structure and behavior. Several factors, such as lipid headgroup charge, hydrocarbon chain packing, monolayer surface pressure and the presence of ions in the subphase modulate protein/monolayer interaction.
Protein insertion into a lipid monolayer results in an expansion of the surface pressure–area isotherm as compared to that of the pure lipid. Such effects have been
Conclusions
Work in the past decade has solidified several salient points in the interactions between amyloidogenic proteins and membranes. The interactions are mutual in that membranes catalyze the formation of protein aggregates, which then destroy the integrity of the membrane that led to their formation. In most cases it is these oligomers rather than mature amyloid fibers that are the toxic species. Both electrostatic interactions with the lipid headgroups and hydrophobic interactions with the
Acknowledgments
This work was partially supported by the University of Genova (Fondi di Ateneo) and a Faculty Research Fellowship Award and sabbaticals from Saint Lawrence University to N. Marano. HypF-N was a kind gift from the labs of Fabrizio Chiti and Massimo Stefani (University of Florence).
References (132)
- et al.
The amyloid state of proteins in human diseases
Cell
(2012) - et al.
Polymorphism in the intermediates and products of amyloid assembly
Curr Opin Struct Biol
(2007) - et al.
A beta(1–40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils
J Mol Biol
(2009) - et al.
Conformational differences between two amyloid beta oligomers of similar size and dissimilar toxicity
J Biol Chem
(2012) - et al.
A beta(1–40) forms five distinct amyloid structures whose beta-sheet contents and fibril stabilities are correlated
J Mol Biol
(2010) - et al.
The role of lipid–protein interactions in amyloid-type protein fibril formation
Chem Phys Lipids
(2006) - et al.
Formation of toxic fibrils of Alzheimer's amyloid beta-protein-(1–40) by monosialoganglioside GM1, a neuronal membrane component
J Mol Biol
(2007) - et al.
Designed fluorescent probes reveal interactions between amyloid-beta(1–40) peptides and G(M1) gangliosides in micelles and lipid vesicles
Biophys J
(2010) - et al.
Kinetic process of beta-amyloid formation via membrane binding
Biophys J
(2010) - et al.
Surface-induced phase separation of a sphingomyelin/cholesterol/ganglioside GM1-planar bilayer on mica surfaces and microdomain molecular conformation that accelerates A beta oligomerization
Biochim Biophys Acta-Biomembr
(2010)
Lipid matrix plays a role in Abeta fibril kinetics and morphology
FEBS Lett
Structural features and cytotoxicity of amyloid oligomers: implications in Alzheimer's disease and other diseases with amyloid deposits
Prog Neurobiol
Peptide–surfactant interactions: consequences for the amyloid-beta structure
Biochem Biophys Res Commun
A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells
Biochim Biophys Acta-Biomembr
Protein aggregation in a membrane environment
Adv Protein Chem Struct Biol
Islet amyloid polypeptide forms rigid lipid–protein amyloid fibrils on supported phospholipid bilayers
J Mol Biol
Surface-catalyzed amyloid fibril formation
J Biol Chem
Collagen plays an active role in the aggregation of beta2-microglobulin under physiopathological conditions of dialysis-related amyloidosis
J Biol Chem
Amphiphilic adsorption of human islet amyloid polypeptide aggregates to lipid/aqueous interfaces
J Mol Biol
Human insulin adsorption kinetics, conformational changes and amyloidal aggregate formation on hydrophobic surfaces
Acta Biomater
The two-fold aspect of the interplay of amyloidogenic proteins with lipid membranes
Chem Phys Lipids
Physicochemical interactions of amyloid [beta]-peptide with lipid bilayers
Biochim Biophys Acta-Biomembr
Amyloid-β membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity
J Mol Biol
Lipid bilayer disruption by oligomeric α-synuclein depends on bilayer charge and accessibility of the hydrophobic core
Biochim Biophys Acta-Biomembr
Binding of beta-amyloid (1–42) peptide to negatively charged phospholipid membranes in the liquid-ordered state: modeling and experimental studies
Biophys J
β-Amyloid (1–40) peptide interactions with supported phospholipid membranes: a single-molecule study
Biophys J
The influence of vesicle size and composition on alpha-synuclein structure and stability
Biophys J
Membrane binding of oligomeric alpha-synuclein depends on bilayer charge and packing
FEBS Lett
Structural and morphological characterization of aggregated species of alpha-synuclein induced by docosahexaenoic acid
J Biol Chem
Alpha-synuclein oligomers with broken helical conformation form lipoprotein nanoparticles
J Biol Chem
Natively folded HypF-N and its early amyloid aggregates interact with phospholipid monolayers and destabilize supported phospholipid bilayers
Biophys J
Islet amyloid polypeptide inserts into phospholipid monolayers as monomer
J Mol Biol
How type II diabetes-related islet amyloid polypeptide damages lipid bilayers
Biophys J
Parameters modulating the maximum insertion pressure of proteins and peptides in lipid monolayers
Biochimie
Surface chemistry of lipid raft and amyloid Aβ (1–40) Langmuir monolayer
Colloids Surf B Biointerfaces
Molecular basis for the glycosphingolipid-binding specificity of alpha-synuclein: key role of tyrosine 39 in membrane insertion
J Mol Biol
Toxic effects of expanded ataxin-1 involve mechanical instability of the nuclear membrane
Biochim Biophys Acta (BBA) — Mol Basis Dis
Soluble amyloid beta-oligomers affect dielectric membrane properties by bilayer insertion and domain formation: implications for cell toxicity
Biophys J
Pore formation by the cytotoxic islet amyloid peptide amylin
J Biol Chem
Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases
J Biol Chem
Protein misfolding, functional amyloid, and human disease
Annu Rev Biochem
Distinguishing crystal-like amyloid fibrils and glass-like amorphous aggregates from their kinetics of formation
Proc Natl Acad Sci U S A
Aggregation phenomena in a system of molecules with two internal states
Phys Rev E
Mysterious oligomerization of the amyloidogenic proteins
FEBS J
Atomic view of a toxic amyloid small oligomer
Science
Toxic fibrillar oligomers of amyloid-β have cross-β structure
Proc Natl Acad Sci U S A
Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils
Science
A causative link between the structure of aberrant protein oligomers and their toxicity
Nat Chem Biol
Phospholipids and Alzheimer's disease: alterations, mechanisms and potential biomarkers
Int J Mol Sci
Surfactant layers at water surfaces
Rep Prog Phys
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