title: Structural basis of aspartylglucosaminuria.
abstract: To elucidate the basis of aspartylglucosaminuria (AGU) from the viewpoint of enzyme structure, we constructed structural models of mutant aspartylglucosaminidase (AGA) proteins using molecular modeling software, TINKER. We classified the amino acid substitutions responsible for AGU and divided them into three groups based on the biochemical phenotype. Then, we examined the structural changes in the AGA protein for each group by calculating the solvent-accessible surface area (ASA), the number of atoms affected, and the root-mean-square deviation (RMSD). Our results revealed that the structural changes in group 1, which exhibits folding/transport defects and a complete deficiency of AGA activity, were generally large and located in the core region of the enzyme molecule. In group 2, exhibiting the mature AGA protein but no AGA activity, the functionally important region of the enzyme molecule was seriously affected. In group 3 exhibiting residual AGA activity, the structural changes in AGA were small and localized near the surface of the enzyme molecule. Coloring of affected atoms based on the distances between the wild-type and mutant ones revealed the characteristic structural changes in the AGA protein geographically and semi-quantitatively. Structural investigation provides us with a deeper insight into the basis of AGU.
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Saito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Kanako
authors.initials: K
authors.lastname: Sugawara
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Togawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D054880:Aspartylglucosaminuria / Q000201:enzymology / Q000235:genetics*; D001227:Aspartylglucosylaminase / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D012984:Software
chemical_list: D001227:Aspartylglucosylaminase