scholarly journals The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding

2013 ◽  
Vol 33 (5) ◽  
Author(s):  
Chi L. L. Pham ◽  
Roberto Cappai
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Membrane Integrity ◽  
Lipid Vesicles ◽  
Helical Conformation ◽  
Unfolded Protein ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

The deposition of α-syn (α-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). α-syn is a natively unfolded protein and adopts an α-helical conformation upon binding to lipid membrane. Oligomeric species of α-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, α-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the α-syn:DA oligomers involves the cross-linking of DA-melanin with α-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced α-syn oligomerization and studied the ability of α-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of α-syn with lipids inhibits the formation of DA-induced α-syn oligomers. Moreover, the α-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of α-syn:DA oligomers may alter the actions of α-syn which require membrane association, leading to disruption of its normal cellular function.

scholarly journals The Properties of α-Synuclein Secondary Nuclei are Dominated by the Solution Conditions Rather than the Seed Fibril Strain

2019 ◽  
Author(s):  
Alessia Peduzzo ◽  
Sara Linse ◽  
Alexander Buell
Keyword(s):  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
The Other ◽  
Secondary Nucleation ◽  
Presynaptic Terminals ◽  
Unfolded Protein ◽  
Primary Nucleation ◽  
Other Hand ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

α-synuclein (α-syn) is a natively unfolded protein predominantly localized in the presynaptic terminals of neurons. It has been shown that α-syn fibrils are the major component of abnormal neuronal aggregates known as Lewy bodies, the characteristic hallmark of Parkinson’s disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is accelerated by suitable surfaces with an affinity for the protein, followed by the elongation of the nuclei by monomer addition. Secondary nucleation, on the other hand, corresponds to the formation of new fibrils when it is facilitated by pre-existing fibrils. While<br>α-synuclein (α-syn) is a natively unfolded protein predominantly localized in the presynaptic terminals of neurons. It has been shown that α-syn fibrils are the major component of abnormal neuronal aggregates known as Lewy bodies, the characteristic hallmark of Parkinson’s disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is accelerated by suitable surfaces with an affinity for the protein, followed by the elongation of the nuclei by monomer addition. Secondary nucleation, on the other hand, corresponds to the formation of new fibrils when it is facilitated by pre-existing fibrils. While it is well-established that the newly added monomer in the process of fibril elongation adopts the conformation of the monomers in the seed, often called templating, it is still unclear under which conditions fibrils formed through secondary nucleation of monomers on the surface of fibrils copy the structure of the parent. Here we show by biochemical and microscopical methods that the secondary nucleation of α-syn, enabled at mildly acidic pH, leads to fibrils that structurally resemble more closely those formed de novo under the same conditions, rather than the seeds if these are formed under different solution condition. This result has important implications for the mechanistic understanding of the secondary nucleation of amyloid fibrils and its role in the propagation of aggregate pathology in protein misfolding diseases.<br>

scholarly journals The Properties of α-Synuclein Secondary Nuclei are Dominated by the Solution Conditions Rather than the Seed Fibril Strain

2019 ◽  
Author(s):  
Alessia Peduzzo ◽  
Sara Linse ◽  
Alexander Buell
Keyword(s):  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
The Other ◽  
Secondary Nucleation ◽  
Presynaptic Terminals ◽  
Unfolded Protein ◽  
Primary Nucleation ◽  
Other Hand ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

α-synuclein (α-syn) is a natively unfolded protein predominantly localized in the presynaptic terminals of neurons. It has been shown that α-syn fibrils are the major component of abnormal neuronal aggregates known as Lewy bodies, the characteristic hallmark of Parkinson’s disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is accelerated by suitable surfaces with an affinity for the protein, followed by the elongation of the nuclei by monomer addition. Secondary nucleation, on the other hand, corresponds to the formation of new fibrils when it is facilitated by pre-existing fibrils. While<br>α-synuclein (α-syn) is a natively unfolded protein predominantly localized in the presynaptic terminals of neurons. It has been shown that α-syn fibrils are the major component of abnormal neuronal aggregates known as Lewy bodies, the characteristic hallmark of Parkinson’s disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is accelerated by suitable surfaces with an affinity for the protein, followed by the elongation of the nuclei by monomer addition. Secondary nucleation, on the other hand, corresponds to the formation of new fibrils when it is facilitated by pre-existing fibrils. While it is well-established that the newly added monomer in the process of fibril elongation adopts the conformation of the monomers in the seed, often called templating, it is still unclear under which conditions fibrils formed through secondary nucleation of monomers on the surface of fibrils copy the structure of the parent. Here we show by biochemical and microscopical methods that the secondary nucleation of α-syn, enabled at mildly acidic pH, leads to fibrils that structurally resemble more closely those formed de novo under the same conditions, rather than the seeds if these are formed under different solution condition. This result has important implications for the mechanistic understanding of the secondary nucleation of amyloid fibrils and its role in the propagation of aggregate pathology in protein misfolding diseases.<br>

scholarly journals Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes

2021 ◽  
Vol 14 (8) ◽  
pp. 746
Author(s):  
Meike Luck ◽  
Markus Fischer ◽  
Maximilian Werle ◽  
Holger A. Scheidt ◽  
Peter Müller
Keyword(s):  
Small Molecule ◽  
Lipid Membranes ◽  
Kinase Inhibitors ◽  
Lipid Membrane ◽  
Membrane Integrity ◽  
Experimental Studies ◽  
Lipid Vesicles ◽  
Protein Kinase Inhibitors ◽  
Log P ◽  
P Value

Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into contact with the plasma and intracellular membranes. Using biophysical methods such as NMR, ESR, and fluorescence spectroscopy in combination with lipid vesicles, we studied the membrane interaction of the kinase inhibitors sunitinib, erlotinib, idelalisib, and lenvatinib; these drugs are characterized by medium log p values, a parameter reflecting the overall hydrophobicity of the molecules, which is one important parameter to predict the interaction with lipid membranes. While all four molecules tend to embed in a similar region of the lipid membrane, their presence has different impacts on membrane structure and dynamics. Most notably, sunitinib, exhibiting the lowest log p value of the four inhibitors, effectively influences membrane integrity, while the others do not. This shows that the estimation of the effect of drug molecules on lipid membranes can be rather complex. In this context, experimental studies on lipid membranes are necessary to (i) identify drugs that may disturb membranes and (ii) characterize drug–membrane interactions on a molecular level. Such knowledge is important for understanding the efficacy and potential side effects of respective drugs.

scholarly journals Human full-length Securin is a natively unfolded protein

2009 ◽  
Vol 14 (6) ◽  
pp. 1410-1418 ◽  
Author(s):  
Nuria Sánchez-Puig ◽  
Dmitry B. Veprintsev ◽  
Alan R. Fersht
Keyword(s):  
Full Length ◽  
Unfolded Protein ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

scholarly journals Physical mechanisms of amyloid nucleation on fluid membranes

2020 ◽  
Vol 117 (52) ◽  
pp. 33090-33098
Author(s):  
Johannes Krausser ◽  
Tuomas P. J. Knowles ◽  
Anđela Šarić
Keyword(s):  
Lipid Membranes ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Physical Mechanisms ◽  
Fluid Membranes ◽  
Protein Membrane ◽  
Protein Rich

Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein–membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways—protein-rich and lipid-rich—and quantify how the membrane fluidity and protein–membrane affinity control the relative importance of those molecular pathways. We find that the membrane’s susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterize the rates and the free-energy profile associated with this heterogeneous nucleation process, in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalyzed amyloid aggregation of α-synuclein, a protein implicated in Parkinson’s disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context.

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