STRUCTURE OF HUMAN BETA-GLUCURONIDASE REVEALS CANDIDATE LYSOSOMAL TARGETING AND ACTIVE-SITE MOTIFS

The X-ray structure of the homotetrameric lysosomal acid hydrolase, hu man beta-glucuronidase (332,000 M(r)), has been determined at 2.6 Angs trom resolution. The tetramer has approximate dihedral symmetry and ea ch protomer consists of three structural domains with topologies simil ar to a jelly roll barrel, an immunoglobulin constant domain and a TIM barrel respectively. Residues 179-204 form a beta-hairpin motif simil ar to the putative lysosomal targeting motif of cathepsin D, supportin g the view that lysosomal targeting has a structural basis. The active site of the enzyme is formed from a large cleft at the interface of t wo monomers. Residues Glu 451 and Glu 540 are proposed to be important for catalysis. The structure establishes a framework for understandin g mutations that lead to the human genetic disease mucopolysaccharidos is VII, and for using the enzyme in anti-cancer therapy.