Human
glucosylcerebrosidase 2 (GBA2) of the CAZy family GH116 is
responsible for the breakdown of glycosphingolipids on the cytoplasmic
face of the endoplasmic reticulum and Golgi apparatus. Genetic defects
in GBA2 result in spastic paraplegia and cerebellar ataxia, while
cross-talk between GBA2 and GBA1 glucosylceramidases may affect Gaucher
disease. Here, we report the first three-dimensional structure for
any GH116 enzyme, Thermoanaerobacterium xylanolyticum TxGH116 β-glucosidase, alone and in complex with diverse ligands.
These structures allow identification of the glucoside binding and
active site residues, which are shown to be conserved with GBA2. Mutagenic
analysis of TxGH116 and structural modeling of GBA2
provide a detailed structural and functional rationale for pathogenic
missense mutations of GBA2.
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