Structural Basis for β-Galactosidase Associated with Lysosomal Disease

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  • リソソーム病原因タンパク質β-ガラクトシダーゼの構造基盤
  • リソソームビョウ ゲンイン タンパクシツv-ガラクトシダーゼ ノ コウゾウ キバン

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Abstract

  GM1-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, GM1 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.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 133 (5), 509-517, 2013-05-01

    The Pharmaceutical Society of Japan

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