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

[gm1 gangliosidosis]

G (M 1 )-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 (M 1 ) 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 .

Diseases
Validation

Diseases presenting "skeletal abnormalities" symptom

22q11.2 deletion syndrome

aromatase deficiency

child syndrome

dentin dysplasia

dentinogenesis imperfecta

erdheim-chester disease

gm1 gangliosidosis

holt-oram syndrome

kabuki syndrome

kallmann syndrome

kindler syndrome

neonatal adrenoleukodystrophy

primary hyperoxaluria type 1

wolf-hirschhorn syndrome

zellweger syndrome

This symptom has already been validated