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Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration.

Burke KA, Yates EA, Legleiter J - Front Neurol (2013)

Bottom Line: Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states.The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions.A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases.

View Article: PubMed Central - PubMed

Affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University Morgantown, WV, USA.

ABSTRACT
There are a vast number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), associated with the rearrangement of specific proteins to non-native conformations that promotes aggregation and deposition within tissues and/or cellular compartments. These diseases are commonly classified as protein-misfolding or amyloid diseases. The interaction of these proteins with liquid/surface interfaces is a fundamental phenomenon with potential implications for protein-misfolding diseases. Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states. Surfaces of particular interest in neurodegenerative diseases are cellular and subcellular membranes that are predominately comprised of lipid components. The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions. Importantly for misfolding diseases, these bilayer properties can not only modulate protein conformation, but also exert influence on aggregation state. A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases. Here, we review the influence of surfaces in driving and stabilizing protein aggregation with a specific emphasis on lipid membranes.

No MeSH data available.


Related in: MedlinePlus

Schematic representations of potential mechanisms of amyloid/lipid association. (A) A schematic representation of simplified, undisrupted bilayer is presented. This bilayer structure can be perturbed by (B) amyloid-protein insertion or (C) association of amphiphilic α-helices lipid-binding domains. Such scenarios could lead to membrane thinning and non-specific membrane leakage. (D) Many amyloid-forming proteins have been shown to form pore-like structures that can act as unregulated ion-selective channels.
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Figure 4: Schematic representations of potential mechanisms of amyloid/lipid association. (A) A schematic representation of simplified, undisrupted bilayer is presented. This bilayer structure can be perturbed by (B) amyloid-protein insertion or (C) association of amphiphilic α-helices lipid-binding domains. Such scenarios could lead to membrane thinning and non-specific membrane leakage. (D) Many amyloid-forming proteins have been shown to form pore-like structures that can act as unregulated ion-selective channels.

Mentions: It has been hypothesized that a potential pathway for Aβ toxicity may lie in its ability to modulate lipid membrane function. This hypothesis is based on the observation that Aβ bears a portion of the APP transmembrane domain. Thus, elucidating the interaction between Aβ and membrane lipids could be critical in understanding potential pathways of Aβ toxicity, especially given the results of studies that demonstrate that changes in membrane composition occur in AD along with the association with plaques, tangles, and neuritic dystrophy. Importantly, it has often been observed that exogenously added Aβ will selectively bind a subset of cells in an apparent homogenous population of cells in culture (Lacor et al., 2004; De Felice et al., 2008). Such an initial cellular binding event may play a critical role in toxic mechanisms and cell to cell propagation of disease. This cell selectivity may be influenced by the presence of specific lipid components or membrane properties (Okada et al., 2007; Wakabayashi and Matsuzaki, 2007; Lin et al., 2008). Once Aβ aggregation begins in or near a membrane, the potential toxic mechanism include disruption of the bilayer structure, changes in bilayer curvature, and/or the creation of membrane pores or channels (Arispe et al., 1993a,b; McLaurin and Chakrabartty, 1996, 1997; Mirzabekov et al., 1996; Gorbenko and Kinnunen, 2006; Figure 4). The majority of studies on membrane-mediated fibrillogenesis have been undertaken with model systems including amyloidogenic peptides or proteins and lipid vesicles or supported bilayers of varying composition (Terzi et al., 1997; Lindstrom et al., 2002; Bokvist et al., 2004; Sparr et al., 2004). These studies often point to the importance of the chemical nature of membrane lipids and the mode of protein–lipid interactions in determining fibrillogenic properties of membrane bound Aβ. Lipids can also stabilize toxic protofibrils and even revert mature fibrils into such toxic species (Martins et al., 2008), providing another potential role for lipid surfaces in toxicity.


Biophysical insights into how surfaces, including lipid membranes, modulate protein aggregation related to neurodegeneration.

Burke KA, Yates EA, Legleiter J - Front Neurol (2013)

Schematic representations of potential mechanisms of amyloid/lipid association. (A) A schematic representation of simplified, undisrupted bilayer is presented. This bilayer structure can be perturbed by (B) amyloid-protein insertion or (C) association of amphiphilic α-helices lipid-binding domains. Such scenarios could lead to membrane thinning and non-specific membrane leakage. (D) Many amyloid-forming proteins have been shown to form pore-like structures that can act as unregulated ion-selective channels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585431&req=5

Figure 4: Schematic representations of potential mechanisms of amyloid/lipid association. (A) A schematic representation of simplified, undisrupted bilayer is presented. This bilayer structure can be perturbed by (B) amyloid-protein insertion or (C) association of amphiphilic α-helices lipid-binding domains. Such scenarios could lead to membrane thinning and non-specific membrane leakage. (D) Many amyloid-forming proteins have been shown to form pore-like structures that can act as unregulated ion-selective channels.
Mentions: It has been hypothesized that a potential pathway for Aβ toxicity may lie in its ability to modulate lipid membrane function. This hypothesis is based on the observation that Aβ bears a portion of the APP transmembrane domain. Thus, elucidating the interaction between Aβ and membrane lipids could be critical in understanding potential pathways of Aβ toxicity, especially given the results of studies that demonstrate that changes in membrane composition occur in AD along with the association with plaques, tangles, and neuritic dystrophy. Importantly, it has often been observed that exogenously added Aβ will selectively bind a subset of cells in an apparent homogenous population of cells in culture (Lacor et al., 2004; De Felice et al., 2008). Such an initial cellular binding event may play a critical role in toxic mechanisms and cell to cell propagation of disease. This cell selectivity may be influenced by the presence of specific lipid components or membrane properties (Okada et al., 2007; Wakabayashi and Matsuzaki, 2007; Lin et al., 2008). Once Aβ aggregation begins in or near a membrane, the potential toxic mechanism include disruption of the bilayer structure, changes in bilayer curvature, and/or the creation of membrane pores or channels (Arispe et al., 1993a,b; McLaurin and Chakrabartty, 1996, 1997; Mirzabekov et al., 1996; Gorbenko and Kinnunen, 2006; Figure 4). The majority of studies on membrane-mediated fibrillogenesis have been undertaken with model systems including amyloidogenic peptides or proteins and lipid vesicles or supported bilayers of varying composition (Terzi et al., 1997; Lindstrom et al., 2002; Bokvist et al., 2004; Sparr et al., 2004). These studies often point to the importance of the chemical nature of membrane lipids and the mode of protein–lipid interactions in determining fibrillogenic properties of membrane bound Aβ. Lipids can also stabilize toxic protofibrils and even revert mature fibrils into such toxic species (Martins et al., 2008), providing another potential role for lipid surfaces in toxicity.

Bottom Line: Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states.The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions.A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases.

View Article: PubMed Central - PubMed

Affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University Morgantown, WV, USA.

ABSTRACT
There are a vast number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), associated with the rearrangement of specific proteins to non-native conformations that promotes aggregation and deposition within tissues and/or cellular compartments. These diseases are commonly classified as protein-misfolding or amyloid diseases. The interaction of these proteins with liquid/surface interfaces is a fundamental phenomenon with potential implications for protein-misfolding diseases. Kinetic and thermodynamic studies indicate that significant conformational changes can be induced in proteins encountering surfaces, which can play a critical role in nucleating aggregate formation or stabilizing specific aggregation states. Surfaces of particular interest in neurodegenerative diseases are cellular and subcellular membranes that are predominately comprised of lipid components. The two-dimensional liquid environments provided by lipid bilayers can profoundly alter protein structure and dynamics by both specific and non-specific interactions. Importantly for misfolding diseases, these bilayer properties can not only modulate protein conformation, but also exert influence on aggregation state. A detailed understanding of the influence of (sub)cellular surfaces in driving protein aggregation and/or stabilizing specific aggregate forms could provide new insights into toxic mechanisms associated with these diseases. Here, we review the influence of surfaces in driving and stabilizing protein aggregation with a specific emphasis on lipid membranes.

No MeSH data available.


Related in: MedlinePlus