title: High resolution crystal structure of human β-glucuronidase reveals structural basis of lysosome targeting.
abstract: Human β-glucuronidase (GUS) cleaves β-D-glucuronic acid residues from the non-reducing termini of glycosaminoglycan and its deficiency leads to mucopolysaccharidosis type VII (MPSVII). Here we report a high resolution crystal structure of human GUS at 1.7 Å resolution and present an extensive analysis of the structural features, unifying recent findings in the field of lysosome targeting and glycosyl hydrolases. The structure revealed several new details including a new glycan chain at Asn272, in addition to that previously observed at Asn173, and coordination of the glycan chain at Asn173 with Lys197 of the lysosomal targeting motif which is essential for phosphotransferase recognition. Analysis of the high resolution structure not only provided new insights into the structural basis for lysosomal targeting but showed significant differences between human GUS, which is medically important in its own right, and E. coli GUS, which can be selectively inhibited in the human gut to prevent prodrug activation and is also widely used as a reporter gene by plant biologists. Despite these differences, both human and E. coli GUS share a high structure homology in all three domains with most of the glycosyl hydrolases, suggesting that they all evolved from a common ancestral gene.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America ; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India.
authors.forename: Md Imtaiyaz
authors.initials: MI
authors.lastname: Hassan
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Grubb
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Klei
authors.forename: Sergey
authors.initials: S
authors.lastname: Korolev
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D005966:Glucuronidase / Q000737:chemistry* / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008969:Molecular Sequence Data
chemical_list: D006025:Glycosaminoglycans; D005966:Glucuronidase