9fjf | pdb_00009fjf

Lysosomal transporting complex of beta-glucocerebrosidase (GCase) and lysosomal integral membrane protein 2 (LIMP-2) with bound Pro-macrobodies (Combined focus map)

spinqualitylabelsall models 9fjf, resolution 3.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fjf is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.7Å Ligands: BMA, MAN, MES, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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