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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

A generic aggregation scheme for amyloid-forming proteins. Proteins fold into their native structure, which is typically a low free energy configuration. However, the energy landscape for protein folding often can have localized minima in which a protein can become trapped into a misfolded conformation, which can lead to aggregation into β-sheet rich amyloid fibrils. The formation of fibrils often proceeds through a heterogeneous mixture of intermediate species, including oligmers and protofibrils. Off-pathway aggregates can also form, such as annular aggregates. These aggregates accumulate into amyloid plaques or inclusions in the diseased brain. The aggregation pathway for any given amyloid-forming protein can vary considerably depending on the protein and its folding environment.
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Figure 1: A generic aggregation scheme for amyloid-forming proteins. Proteins fold into their native structure, which is typically a low free energy configuration. However, the energy landscape for protein folding often can have localized minima in which a protein can become trapped into a misfolded conformation, which can lead to aggregation into β-sheet rich amyloid fibrils. The formation of fibrils often proceeds through a heterogeneous mixture of intermediate species, including oligmers and protofibrils. Off-pathway aggregates can also form, such as annular aggregates. These aggregates accumulate into amyloid plaques or inclusions in the diseased brain. The aggregation pathway for any given amyloid-forming protein can vary considerably depending on the protein and its folding environment.

Mentions: A common motif of several neurodegenerative diseases is the ordered aggregation of specific proteins, leading to their deposition in tissues or cellular compartments (Chiti and Dobson, 2006). Often referred to as protein conformational or misfolding disorders, such diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyloidoses, α1-antitrypsin deficiency, and the prion encephalopathies to name a few. The common structural motif of protein aggregates associated with these diseases is the formation of extended, β-sheet rich fibrils, referred to as amyloid. Despite no apparent correlation between aggregating proteins in size or primary amino acid sequence, the characteristic lesions of each disease typically contain fibrillar structures with common biochemical characteristics (Dobson, 2003; Chiti and Dobson, 2006), indicating the potential for a conserved mechanism of pathogenesis linking these phenotypically diverse diseases. The earliest potential event in the disease process may be the conversion of a protein to a critical abnormal conformation, resulting in toxic gain of function for the monomer, and/or the formation of toxic nanoscale aggregates (Figure 1; Naeem and Fazili, 2011). The elusive toxic species, whether monomeric or higher-order, may subsequently initiate a cascade of pathogenic protein–protein interactions that culminate in neuronal dysfunction. The precise timing of such interactions and the mechanisms by which altered protein conformations or aggregates trigger neuronal dysfunction are unclear.


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

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

A generic aggregation scheme for amyloid-forming proteins. Proteins fold into their native structure, which is typically a low free energy configuration. However, the energy landscape for protein folding often can have localized minima in which a protein can become trapped into a misfolded conformation, which can lead to aggregation into β-sheet rich amyloid fibrils. The formation of fibrils often proceeds through a heterogeneous mixture of intermediate species, including oligmers and protofibrils. Off-pathway aggregates can also form, such as annular aggregates. These aggregates accumulate into amyloid plaques or inclusions in the diseased brain. The aggregation pathway for any given amyloid-forming protein can vary considerably depending on the protein and its folding environment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A generic aggregation scheme for amyloid-forming proteins. Proteins fold into their native structure, which is typically a low free energy configuration. However, the energy landscape for protein folding often can have localized minima in which a protein can become trapped into a misfolded conformation, which can lead to aggregation into β-sheet rich amyloid fibrils. The formation of fibrils often proceeds through a heterogeneous mixture of intermediate species, including oligmers and protofibrils. Off-pathway aggregates can also form, such as annular aggregates. These aggregates accumulate into amyloid plaques or inclusions in the diseased brain. The aggregation pathway for any given amyloid-forming protein can vary considerably depending on the protein and its folding environment.
Mentions: A common motif of several neurodegenerative diseases is the ordered aggregation of specific proteins, leading to their deposition in tissues or cellular compartments (Chiti and Dobson, 2006). Often referred to as protein conformational or misfolding disorders, such diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyloidoses, α1-antitrypsin deficiency, and the prion encephalopathies to name a few. The common structural motif of protein aggregates associated with these diseases is the formation of extended, β-sheet rich fibrils, referred to as amyloid. Despite no apparent correlation between aggregating proteins in size or primary amino acid sequence, the characteristic lesions of each disease typically contain fibrillar structures with common biochemical characteristics (Dobson, 2003; Chiti and Dobson, 2006), indicating the potential for a conserved mechanism of pathogenesis linking these phenotypically diverse diseases. The earliest potential event in the disease process may be the conversion of a protein to a critical abnormal conformation, resulting in toxic gain of function for the monomer, and/or the formation of toxic nanoscale aggregates (Figure 1; Naeem and Fazili, 2011). The elusive toxic species, whether monomeric or higher-order, may subsequently initiate a cascade of pathogenic protein–protein interactions that culminate in neuronal dysfunction. The precise timing of such interactions and the mechanisms by which altered protein conformations or aggregates trigger neuronal dysfunction are unclear.

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