Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2

Jan Philipp Dobert, Jan-Hannes Schäfer, Thomas Dal Maso, Priyadarshini Ravindran, Dustin J. E. Huard, Eileen Socher, Lisa A. Schildmeyer, Raquel L. Lieberman, Wim Versées, Arne Moeller, Friederike Zunke () and Philipp Arnold ()
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Jan Philipp Dobert: Friedrich-Alexander-University Erlangen-Nürnberg (FAU)
Jan-Hannes Schäfer: Osnabrück University
Thomas Dal Maso: Pleinlaan 2
Priyadarshini Ravindran: Friedrich-Alexander-University Erlangen-Nürnberg (FAU)
Dustin J. E. Huard: Georgia Institute of Technology
Eileen Socher: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Lisa A. Schildmeyer: Georgia Institute of Technology
Raquel L. Lieberman: Georgia Institute of Technology
Wim Versées: Pleinlaan 2
Arne Moeller: Osnabrück University
Friederike Zunke: Friedrich-Alexander-University Erlangen-Nürnberg (FAU)
Philipp Arnold: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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 and two GCase-targeted pro-macrobodies. We identify helix 5 and helix 7 of LIMP-2 to interact with a binding pocket in GCase, forming a mostly hydrophobic interaction interface supported by one essential salt bridge. Understanding the interplay of GCase and LIMP-2 on a structural level is crucial to identify potential activation sites and conceptualizing novel therapeutic approaches targeting GCase. Here, we unveil the protein structure of a mannose-6-phosphate-independent lysosomal transport complex and provide fundamental knowledge for translational clinical research to overcome GD and PD.

Date: 2025
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DOI: 10.1038/s41467-025-58340-1

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