title: [Structural basis for β-galactosidase associated with lysosomal disease].
abstract: G(M1)-gangliosidosis and Morquio B are rare lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme human β-D-galactosidase (h-β-GAL), which lead to accumulations of the h-β-GAL substrates, G(M1) ganglioside and keratan sulfate due to mutations in the h-β-GAL gene. H-β-GAL is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose residues. Here, we present the crystal structures of h-β-GAL in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. H-β-GAL showed a novel homodimer structure; each monomer was comprised of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2. The long loop region connecting the TIM barrel domain with β-domain 1 was responsible for the dimerization. To gain structural insight into the molecular defects of h-β-GAL in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed.
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo. shimizu@mol.f.u-tokyo.ac.jp
authors: Toshiyuki
authors: T
authors: Shimizu
mesh_terms: D000818:Animals; D005732:Gangliosides / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000235:genetics; D006801:Humans; D007632:Keratan Sulfate / Q000378:metabolism; D016464:Lysosomal Storage Diseases / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008968:Molecular Conformation; D009085:Mucopolysaccharidosis IV / Q000235:genetics; D009154:Mutation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D001616:beta-Galactosidase / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*
chemical_list: D005732:Gangliosides; D007632:Keratan Sulfate; D001616:beta-Galactosidase