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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

Aβ aggregation is modulated by the presence of chemically distinct solid surfaces. (A) On highly ordered pyrolytic graphite, Aβ aggregates into extended nanoribbons that are epitaxially ordered on the surface. The distinct orientation of Aβ aggregates on graphite is attributed to the optimization of the contact between the peptide and underlying hydrophobic carbon lattice. (B) On a negatively charged, hydrophilic mica surface, Aβ forms discrete oligomers that maintained some lateral mobility along the plane of the surface. These oligomers could organize into elongated protofibrillar structures. Schematic representations of the structure of each surface (graphite and mica) are provided under each image.
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Figure 2: Aβ aggregation is modulated by the presence of chemically distinct solid surfaces. (A) On highly ordered pyrolytic graphite, Aβ aggregates into extended nanoribbons that are epitaxially ordered on the surface. The distinct orientation of Aβ aggregates on graphite is attributed to the optimization of the contact between the peptide and underlying hydrophobic carbon lattice. (B) On a negatively charged, hydrophilic mica surface, Aβ forms discrete oligomers that maintained some lateral mobility along the plane of the surface. These oligomers could organize into elongated protofibrillar structures. Schematic representations of the structure of each surface (graphite and mica) are provided under each image.

Mentions: Due to the ability of AFM to be operated in solution and track the formation and fate of individual aggregates with time on surfaces (Goldsbury et al., 1999), the impact of surface chemistry on the morphology of Aβ aggregates has been extensively studied with this technique. On mica, a hydrophilic surface, Aβ(1–40) (Blackley et al., 2000) and Aβ(1–42) (Kowalewski and Holtzman, 1999) form small, highly mobile oligomeric aggregates that organize into extended pre-fibrillar aggregates that continually elongate with time (Figure 2A). These aggregate structures are similar in morphology to those formed in bulk solution from similarly prepped Aβ stocks (Kowalewski and Holtzman, 1999; Legleiter and Kowalewski, 2004). However, Aβ(1–42) aggregates into morphologically distinct structures on a graphite surface (Figure 2B), forming extended nanoribbons with heights of ∼1–1.2 nm and widths of ∼18 nm (Kowalewski and Holtzman, 1999). These dimensions suggest that Aβ adopts a fully extended β-sheet conformation perpendicular to the long axis of the nanoribbons. These nanoribbons elongated with time, organize themselves into parallel, raft-like structures with a preferential alignment along the graphite lattice. Aβ adsorbs to and aggregates on surfaces functionalized with methyl, carboxyl, or amine groups; however, aggregate morphology and surface affinity is dependent on the specific surface chemistries (Moores et al., 2011). Hydrophobic surfaces promote formation of spherical amorphous clusters; charged surfaces promote the formation of protofibrils (Moores et al., 2011). Studies of the aggregation of Aβ peptides containing single point mutations on mica further support the notion that electrostatics play an important role in Aβ adsorption and aggregation on surfaces (Yates et al., 2011). These mutations are clustered around the central hydrophobic core of Aβ (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation) and are associated with familial forms of AD. In bulk solution and under identical preparatory conditions, these Aβ mutants form aggregated species that were morphologically similar to those of Wild Type Aβ; however, on a mica surface the aggregates differ in morphology (Figure 3). While Wild Type Aβ forms oligomers and putative protofibrils on mica similar to other previously described studies, Arctic Aβ aggregate into extended, fibrillar aggregates on mica that orient on the surface similar to the previously described Wild Type Aβ aggregates on graphite. However, the dimensions of the Arctic Aβ aggregates on mica indicate they most likely contain a β-turn as opposed to the fully elongated Wild Type Aβ nanoribbons on graphite. Italian Aβ, which replaces a negatively charged residue with a positive one, adsorbs quickly to mica and predominantly forms oligomeric aggregates reminiscent of those formed by wild type Aβ on mica. However, there was a small percentage of Italian Aβ aggregates similar in morphology to those formed by Arctic Aβ on mica.


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

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

Aβ aggregation is modulated by the presence of chemically distinct solid surfaces. (A) On highly ordered pyrolytic graphite, Aβ aggregates into extended nanoribbons that are epitaxially ordered on the surface. The distinct orientation of Aβ aggregates on graphite is attributed to the optimization of the contact between the peptide and underlying hydrophobic carbon lattice. (B) On a negatively charged, hydrophilic mica surface, Aβ forms discrete oligomers that maintained some lateral mobility along the plane of the surface. These oligomers could organize into elongated protofibrillar structures. Schematic representations of the structure of each surface (graphite and mica) are provided under each image.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Aβ aggregation is modulated by the presence of chemically distinct solid surfaces. (A) On highly ordered pyrolytic graphite, Aβ aggregates into extended nanoribbons that are epitaxially ordered on the surface. The distinct orientation of Aβ aggregates on graphite is attributed to the optimization of the contact between the peptide and underlying hydrophobic carbon lattice. (B) On a negatively charged, hydrophilic mica surface, Aβ forms discrete oligomers that maintained some lateral mobility along the plane of the surface. These oligomers could organize into elongated protofibrillar structures. Schematic representations of the structure of each surface (graphite and mica) are provided under each image.
Mentions: Due to the ability of AFM to be operated in solution and track the formation and fate of individual aggregates with time on surfaces (Goldsbury et al., 1999), the impact of surface chemistry on the morphology of Aβ aggregates has been extensively studied with this technique. On mica, a hydrophilic surface, Aβ(1–40) (Blackley et al., 2000) and Aβ(1–42) (Kowalewski and Holtzman, 1999) form small, highly mobile oligomeric aggregates that organize into extended pre-fibrillar aggregates that continually elongate with time (Figure 2A). These aggregate structures are similar in morphology to those formed in bulk solution from similarly prepped Aβ stocks (Kowalewski and Holtzman, 1999; Legleiter and Kowalewski, 2004). However, Aβ(1–42) aggregates into morphologically distinct structures on a graphite surface (Figure 2B), forming extended nanoribbons with heights of ∼1–1.2 nm and widths of ∼18 nm (Kowalewski and Holtzman, 1999). These dimensions suggest that Aβ adopts a fully extended β-sheet conformation perpendicular to the long axis of the nanoribbons. These nanoribbons elongated with time, organize themselves into parallel, raft-like structures with a preferential alignment along the graphite lattice. Aβ adsorbs to and aggregates on surfaces functionalized with methyl, carboxyl, or amine groups; however, aggregate morphology and surface affinity is dependent on the specific surface chemistries (Moores et al., 2011). Hydrophobic surfaces promote formation of spherical amorphous clusters; charged surfaces promote the formation of protofibrils (Moores et al., 2011). Studies of the aggregation of Aβ peptides containing single point mutations on mica further support the notion that electrostatics play an important role in Aβ adsorption and aggregation on surfaces (Yates et al., 2011). These mutations are clustered around the central hydrophobic core of Aβ (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation) and are associated with familial forms of AD. In bulk solution and under identical preparatory conditions, these Aβ mutants form aggregated species that were morphologically similar to those of Wild Type Aβ; however, on a mica surface the aggregates differ in morphology (Figure 3). While Wild Type Aβ forms oligomers and putative protofibrils on mica similar to other previously described studies, Arctic Aβ aggregate into extended, fibrillar aggregates on mica that orient on the surface similar to the previously described Wild Type Aβ aggregates on graphite. However, the dimensions of the Arctic Aβ aggregates on mica indicate they most likely contain a β-turn as opposed to the fully elongated Wild Type Aβ nanoribbons on graphite. Italian Aβ, which replaces a negatively charged residue with a positive one, adsorbs quickly to mica and predominantly forms oligomeric aggregates reminiscent of those formed by wild type Aβ on mica. However, there was a small percentage of Italian Aβ aggregates similar in morphology to those formed by Arctic Aβ on mica.

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