Transport of Alzheimer’s Associated Amyloid-β Catalyzed by P-glycoprotein
説明
<jats:title>ABSTRACT</jats:title><jats:p>P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer’s disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer’s associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In<jats:italic>in vitro</jats:italic>assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD.</jats:p>
収録刊行物
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- PLOS ONE
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PLOS ONE 16 e0250371-, 2020-10-22
Cold Spring Harbor Laboratory
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キーワード
- Science
- Molecular Dynamics Simulation
- Ligands
- Substrate Specificity
- Adenosine Triphosphate
- Protein Domains
- Alzheimer Disease
- Cell Line, Tumor
- Humans
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Amyloid beta-Peptides
- Hydrolysis
- Q
- R
- Peptide Fragments
- Molecular Docking Simulation
- Protein Transport
- Blood-Brain Barrier
- Biocatalysis
- Disease Progression
- Quinolines
- Medicine
- Protein Conformation, beta-Strand
- Protein Binding
- Signal Transduction