ArticleThe Journal of biological chemistry2015
Structural features of membrane-bound glucocerebrosidase and α-synuclein probed by neutron reflectometry and fluorescence spectroscopy.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 49 citations in OpenAlex.
- Sphingolipidoses: expanding the spectrum of α-synucleinopathies.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Investigating the Impact of the Parkinson's-Associated GBA1 E326K Mutation on β-Glucocerebrosidase Dimerization and Interactome Dynamics Through an In Silico Approach.International journal of molecular sciences · 2024Article
- Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease.Translational neurodegeneration · 2024Review
- Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies.Metabolites · 2024Review
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Binding Behavior between Transforming-Growth-Factor-Beta1 and Its Receptor Reconstituted in Biomimetic Membranes.Membranes · 2023Article
- Review
- Neuronopathic Gaucher disease: Beyond lysosomal dysfunction.Frontiers in molecular neuroscience · 2022Review
- The cell biology of Parkinson's disease.The Journal of cell biology · 2021Review
- Membrane Interactions of α-Synuclein Probed by Neutrons and Photons.Accounts of chemical research · 2021Article
- Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson's disease and their targeted therapeutic approaches: a comprehensive review.Translational neurodegeneration · 2021Review
- Biomembrane Structure and Material Properties Studied With Neutron Scattering.Frontiers in chemistry · 2021Review
- Article
- Information gain from isotopic contrast variation in neutron reflectometry on protein-membrane complex structures.Journal of applied crystallography · 2020Article
- Glucocerebrosidase as a therapeutic target for Parkinson's disease.Expert opinion on therapeutic targets · 2020Review
- Post-translational protein modifications in schizophrenia.NPJ schizophrenia · 2020Review
- C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease.The Journal of biological chemistry · 2019Article
- Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated α-synuclein.The Journal of biological chemistry · 2018Article
- Role of GSK3β/α-synuclein axis in methamphetamine-induced neurotoxicity in PC12 cells.Toxicology research · 2018Article
- Lysosomal integral membrane protein-2 as a phospholipid receptor revealed by biophysical and cellular studies.Nature communications · 2017Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in glucocerebrosidase (GCase), the enzyme deficient in Gaucher disease, are a common genetic risk factor for the development of Parkinson disease and related disorders, implicating the role of this lysosomal hydrolase in the disease etiology. A specific physical interaction exists between the Parkinson disease-related protein α-synuclein (α-syn) and GCase both in solution and on the lipid membrane, resulting in efficient enzyme inhibition. Here, neutron reflectometry was employed as a first direct structural characterization of GCase and α-syn·GCase complex on a sparsely-tethered lipid bilayer, revealing the orientation of the membrane-bound GCase. GCase binds to and partially inserts into the bilayer with its active site most likely lying just above the membrane-water interface. The interaction was further characterized by intrinsic Trp fluorescence, circular dichroism, and surface plasmon resonance spectroscopy. Both Trp fluorescence and neutron reflectometry results suggest a rearrangement of loops surrounding the catalytic site, where they extend into the hydrocarbon chain region of the outer leaflet. Taking advantage of contrasting neutron scattering length densities, the use of deuterated α-syn versus protiated GCase showed a large change in the membrane-bound structure of α-syn in the complex. We propose a model of α-syn·GCase on the membrane, providing structural insights into inhibition of GCase by α-syn. The interaction displaces GCase away from the membrane, possibly impeding substrate access and perturbing the active site. GCase greatly alters membrane-bound α-syn, moving helical residues away from the bilayer, which could impact the degradation of α-syn in the lysosome where these two proteins interact.
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