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 Mr), has been determined at 2.6 A resolution. The tetramer has approximate dihedral symmetry and each promoter 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.
Jain
S
S
Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
Drendel
W B
WB
Chen
Z W
ZW
Mathews
F S
FS
Sly
W S
WS
Grubb
J H
JH
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005966:Glucuronidase / Q000737:chemistry*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment
D005966:Glucuronidase