ArticleProceedings of the National Academy of Sciences of the United States of America2016
Characterization of the complex formed by β-glucocerebrosidase and the lysosomal integral membrane protein type-2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 65 citations in OpenAlex.
- Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 CaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A Common PD-RiskbioRxiv : the preprint server for biology · 2025Article
- Gaucher disease, state of the art and perspectives.Journal of internal medicine · 2025Review
- Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.Nature communications · 2025Article
- Prioritizing Parkinson's disease risk genes in genome-wide association loci.NPJ Parkinson's disease · 2025Article
- Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2.Nature communications · 2025Article
- 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
- Activation and Purification of ß-Glucocerebrosidase by Exploiting its Transporter LIMP-2 - Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The annotation ofScience advances · 2024Article
- Pathological Functions of Lysosomal Ion Channels in the Central Nervous System.International journal of molecular sciences · 2024Review
- Cellular depletion of major cathepsin proteases reveals their concerted activities for lysosomal proteolysis.Cellular and molecular life sciences : CMLS · 2024Article
- Characterization of Novel Human β-glucocerebrosidase Antibodies for Parkinson's Disease Research.Journal of Parkinson's disease · 2024Article
- iPSC-derived neural precursor cells engineeringMolecular therapy. Methods & clinical development · 2023Article
- Review
- HEPES-buffering of bicarbonate-containing culture medium perturbs lysosomal glucocerebrosidase activity.Journal of cellular biochemistry · 2022Article
- Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy.Molecular neurobiology · 2022Article
- TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.Neuron · 2021Article
- Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Gaucher disease: Basic and translational science needs for more complete therapy and management.Molecular genetics and metabolism · 2021Review
- Fibroblasts from idiopathic Parkinson's disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2.Molecular brain · 2021Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of β-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding. Here, we identified a similar helical motif in GC through surface potential analysis. Coimmunoprecipitation and immunofluorescence studies revealed a triple-helical interface region within GC as critical for LIMP-2 binding and lysosomal transport. Based on these findings, we generated a LIMP-2 helix 5-derived peptide that precipitated and activated recombinant wild-type and GD-associated N370S mutant GC in vitro. The helix 5 peptide fused to a cell-penetrating peptide also activated endogenous lysosomal GC and reduced α-synuclein levels, suggesting that LIMP-2-derived peptides can be used to activate endogenous as well as recombinant wild-type or mutant GC efficiently. Our data also provide a structural model of the LIMP-2/GC complex that will facilitate the development of GC chaperones and activators as potential therapeutics for GD, PD, and related synucleinopathies.
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