Abstract
G(M1) gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme β-d-galactosidase (β-Gal), which lead to accumulations of the β-Gal substrates, G(M1) ganglioside, and keratan sulfate. β-Gal is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose residues. This study shows the crystal structures of human β-Gal in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. Human β-Gal is composed of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2. To gain structural insight into the molecular defects of 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.
Highlights
Deficiencies in -D-galactosidase cause lysosomal storage diseases
GM1 gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively
These diseases are caused by deficiencies in the lysosomal enzyme -D-galactosidase (-Gal), which lead to accumulations of the -Gal substrates, GM1 ganglioside, and keratan sulfate. -Gal is an exoglycosidase that catalyzes the hydrolysis of terminal -linked galactose residues
Summary
Deficiencies in -D-galactosidase cause lysosomal storage diseases. Results: This is the first report to describe the crystal structure of human -Gal. GM1 gangliosidosis and Morquio B are autosomal recessive lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme -D-galactosidase (-Gal), which lead to accumulations of the -Gal substrates, GM1 ganglioside, and keratan sulfate. Studies are needed to elucidate the effects of the various pathogenic mutations in -Gal in terms of the protein structure as well as to gain insights into the structural characterization and catalytic mechanism of -Gal. Here we report the first crystal structures of human -Gal in complex with its catalytic product galactose and with its inhibitor 1-deoxygalactonojirimycin (DGJ)
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