[Structural basis for β-galactosidase associated with lysosomal disease]

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Context:

• G(M1)-gangliosidosis and Morquio B are rare lysosomal storage diseases.
• These conditions result from deficiencies in human β-D-galactosidase (h-β-GAL).
• Mutations in the h-β-GAL gene cause enzyme deficiency, leading to substrate accumulation.

Purpose:

• To determine the crystal structure of h-β-GAL.
• To elucidate the structural basis of h-β-GAL function and disease-causing mutations.
• To provide insights into the molecular defects underlying G(M1)-gangliosidosis and Morquio B.

Summary:

• The crystal structures of h-β-GAL with its product galactose and inhibitor 1-deoxygalactonojirimycin were determined.
• h-β-GAL forms a novel homodimer structure with distinct catalytic and β-domains.
• Disease-associated mutations were mapped onto the structure, aiding in understanding molecular pathology.

Impact:

• Provides a structural understanding of h-β-GAL, crucial for studying lysosomal storage diseases.
• Identifies the dimerization interface and domain organization of h-β-GAL.
• Facilitates the development of targeted therapies for G(M1)-gangliosidosis and Morquio B.