Crystal structure of human β-galactosidase: structural basis of Gm1 gangliosidosis and morquio B diseases

• Published in: The Journal of biological chemistry Vol. 287; no. 3; pp. 1801 - 1812
• Main Authors: Ohto, Umeharu, Usui, Kimihito, Ochi, Toshinari, Yuki, Kenjiro, Satow, Yoshinori, Shimizu, Toshiyuki
• Format: Journal Article
• Language: English
• Published: United States 13.01.2012
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemistry; beta-Galactosidase - chemistry; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Crystallography, X-Ray; G(M1) Ganglioside - genetics; G(M1) Ganglioside - metabolism; Galactose - chemistry; Galactose - genetics; Galactose - metabolism; Gangliosidosis, GM1 - enzymology; Gangliosidosis, GM1 - genetics; Humans; Hydrolysis; Keratan Sulfate - genetics; Keratan Sulfate - metabolism; Lysosomes - enzymology; Lysosomes - genetics; Models, Molecular; Mucopolysaccharidosis IV - enzymology; Mucopolysaccharidosis IV - genetics; Mutation; Protein Structure, Tertiary
• ISSN: 1083-351X
• DOI: 10.1074/jbc.M111.293795

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.