Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs

The X-ray structure of the homotetrameric lysosomal acid hydrolase, human beta-glucuronidase (332,000 M(r)), has been determined at 2.6 Angstrom resolution. The tetramer has approximate dihedral symmetry and each protomer consists of three structural domains with topologies similar to a jelly roll barrel, an immunoglobulin constant domain and a TIM barrel respectively. Residues 179-204 form a beta-hairpin motif similar to the putative lysosomal targeting motif of cathepsin D, supporting 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 two monomers. Residues Glu 451 and Glu 540 are proposed to be important for catalysis. The structure establishes a framework for understanding mutations that lead to the human genetic disease mucopolysaccharidosis VII, and for using the enzyme in anti-cancer therapy.