Structural highlights
Disease
SCRB2_HUMAN Unverricht-Lundborg disease;Gaucher disease type 1;Action myoclonus - renal failure syndrome. The disease is caused by mutations affecting the gene represented in this entry. Genetic variants in SCARB2 can act as modifier of the phenotypic expression and severity of Gaucher disease.
Function
SCRB2_HUMAN Acts as a lysosomal receptor for glucosylceramidase (GBA) targeting.[1]
Publication Abstract from PubMed
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 beta-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.
Cryo-TEM structure of beta-glucocerebrosidase in complex with its transporter LIMP-2.,Dobert JP, Schafer JH, Dal Maso T, Ravindran P, Huard DJE, Socher E, Schildmeyer LA, Lieberman RL, Versees W, Moeller A, Zunke F, Arnold P Nat Commun. 2025 Mar 30;16(1):3074. doi: 10.1038/s41467-025-58340-1. PMID:40159502[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Reczek D, Schwake M, Schroder J, Hughes H, Blanz J, Jin X, Brondyk W, Van Patten S, Edmunds T, Saftig P. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007 Nov 16;131(4):770-83. PMID:18022370 doi:http://dx.doi.org/10.1016/j.cell.2007.10.018
- ↑ Dobert JP, Schäfer JH, Dal Maso T, Ravindran P, Huard DJE, Socher E, Schildmeyer LA, Lieberman RL, Versées W, Moeller A, Zunke F, Arnold P. Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2. Nat Commun. 2025 Mar 30;16(1):3074. PMID:40159502 doi:10.1038/s41467-025-58340-1
