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

Dobert J, Schäfer JH, Dal Maso T, Ravindran P, Huard DJE, Socher E, Schildmeyer LA, Lieberman RL, Versées W, Moeller A, Zunke F, Arnold P (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 3074

Issue: 1

DOI: 10.1038/s41467-025-58340-1

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.

Authors with CRIS profile

Jan Dobert Department of Molecular Neurology Priyadarshini Ravindran Department of Molecular Neurology Eileen Socher Lehrstuhl für Funktionelle und Klinische Anatomie Friederike Zunke Juniorprofessur für Translationale Neurowissenschaften Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie

Involved external institutions

Georgia Institute of Technology US United States (USA) (US) Universität Osnabrück DE Germany (DE) Vrije Universiteit Brussel (VUB) BE Belgium (BE)

How to cite

APA:

Dobert, J., Schäfer, J.-H., Dal Maso, T., Ravindran, P., Huard, D.J.E., Socher, E.,... Arnold, P. (2025). Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2. Nature Communications, 16. https://doi.org/10.1038/s41467-025-58340-1

MLA:

Dobert, Jan, et al. "Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2." Nature Communications 16 (2025).

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