biostudies-literatureDobert JPMichael J. Fox Foundation for Parkinson's ResearchMichael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation)3074https://www.ebi.ac.uk/biostudies/studies/S-EPMC11955523biostudies-literatureUnknown16(1)Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via the mannose-6-phosphate receptor pathway. One of the few known exceptions is the enzyme β-glucocerebrosidase (GCase) that requires the lysosomal integral membrane protein type-2 (LIMP-2) as a proprietary lysosomal transporter. Genetic variations in the GCase encoding gene GBA1 cause Gaucher's disease (GD) and present the highest genetic risk factor to develop Parkinson's disease (PD). Activators targeting GCase emerge as a promising therapeutic approach to treat GD and PD, with pre-clinical and clinical trials ongoing. In this study, we resolve the complex of GCase and LIMP-2 using cryo-electron microscopy with the aid of an engineered LIMP-2 shuttle Nature communicationsCryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2.PMC11955523MJFF-17240MJFF-16697MJFF-020706MJFF-019371MJFF-022745Dobert JPRavindran PSchildmeyer LALieberman RLSchafer JHHuard DJEMoeller AZunke FVersees WArnold PDal Maso TSocher EfalseCryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2.Targeting proteins to their final cellular destination requires transport mechanisms and nearly all lysosomal enzymes reach the lysosome via the mannose-6-phosphate receptor pathway. One of the few known exceptions is the enzyme β-glucocerebrosidase (GCase) that requires the lysosomal integral membrane protein type-2 (LIMP-2) as a proprietary lysosomal transporter. Genetic variations in the GCase encoding gene GBA1 cause Gaucher's disease (GD) and present the highest genetic risk factor to develop Parkinson's disease (PD). Activators targeting GCase emerge as a promising therapeutic approach to treat GD and PD, with pre-clinical and clinical trials ongoing. In this study, we resolve the complex of GCase and LIMP-2 using cryo-electron microscopy with the aid of an engineered LIMP-2 shuttle 2025-01-01T00:00:00Z2025 Mar2026-06-01T10:14:56.128Z2025-07-13T03:04:44.775ZS-EPMC119555234015950210.1038/s41467-025-58340-1