Structural and clinical implications of amino acid substitutions in α-L-iduronidase: insight into the basis of mucopolysaccharidosis type I.
Allelic mutations, predominantly missense ones, of the α-l-iduronidase (IDUA) gene cause mucopolysaccharidosis type I (MPS I), which exhibits heterogeneous phenotypes. These phenotypes are basically classified into severe, intermediate, and attenuated types. We previously examined the structural changes in IDUA due to MPS I by homology modeling, but the reliability was limited because of the low sequence identity. In this study, we built new structural models of mutant IDUAs due to 57 amino acid substitutions that had been identified in 27 severe, 1 severe-intermediate, 13 intermediate, 1 attenuated-intermediate and 15 attenuated type MPS I patients based on the crystal structure of human IDUA, which was recently determined by us. The structural changes were examined by calculating the root-mean-square distances (RMSD) and the number of atoms influenced by the amino acid replacements. The results revealed that the structural changes of the enzyme protein tended to be correlated with the severity of the disease. Then we focused on the structural changes resulting from amino acid replacements in the immunoglobulin-like domain and adjacent region, of which the structure had been missing in the IDUA model previously built. Coloring of atoms influenced by an amino acid substitution was performed in each case and the results revealed that the structural changes occurred in a region far from the active site of IDUA, suggesting that they affected protein folding. Structural analysis is thus useful for elucidation of the basis of MPS I.
Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan.
Seiji
S
Saito
NPO for the Promotion of Research on Intellectual Property Tokyo, Tokyo, Japan.
Kazuki
K
Ohno
Laboratory of X-ray Crystallography, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
Nobuo
N
Maita
Department of Clinical Genetics, Meiji Pharmaceutical University, Tokyo, Japan. Electronic address: sakuraba@my-pharm.ac.jp.
Hitoshi
H
Sakuraba
D019943:Amino Acid Substitution; D020134:Catalytic Domain; D015870:Gene Expression; D006801:Humans; D007068:Iduronidase / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D008958:Models, Molecular; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012720:Severity of Illness Index; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
D007068:Iduronidase
Amino acid substitution; Mucopolysaccharidosis type I; Structural model; α-l-Iduronidase