Structural study on mutant α-l-iduronidases: insight into mucopolysaccharidosis type I

Abstract

To elucidate the basis of mucopolysaccharidosis type I (MPS I), we constructed structural models of mutant a-L-iduronidases (IDUAs) resulting from 33 amino acid substitutions that lead to MPS I (17 severe, eight intermediate, and eight attenuated). Then, we examined the structural changes in the enzyme protein by calculating the number of atoms affected and determined the root-meansquare distance (RMSD) and the solvent-accessible surface area (ASA). In the severe MPS I group, the number of atoms influenced by a mutation and the average RMSD value were larger than those in the attenuated group, and the residues associated with the mutations identified in the severe group tended to be less solvent accessible than those in the attenuated group. The clinically intermediate phenotype group exhibited intermediate values for the numbers of atoms affected, RMSD, and ASA between those in the severe group and those in the attenuated group. The results indicated that large structural changes had occurred in the core region in the severe MPS I group and small ones on the molecular surface in the attenuated MPS I group. Color imaging revealed the distributions and degrees of the structural changes caused by representative mutations for MPS I. Thus, structural analysis is useful for elucidating the basis of MPS I. As there was a difference in IDUA structural change between the severe MPS I group and the attenuated one, except for a couple of mutations, structural analysis can help predict the clinical outcome of the disease.

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

“…[18][19][20][21][22] We defined that the structure was influenced by an amino acid substitution when the position of an atom in a mutant differed from that in the wild-type structure by more than the cut-off distance (0.15 Å ) on the basis of the total root-mean-square distance (RMSD), as described earlier. [18][19][20][21][22] The numbers of influenced atoms in the main chain and the side chain were calculated. Abbreviations: ASA, solvent-accessible surface area; RMSD, root-mean-square distance; À, no protein; ¼, normal amount; m, more than normal; k, less than normal.…”

“…20,22,23 Determination of the solvent-accessible surface area (ASA) values of amino acid residues causing a processing/transport defect in Pompe disease…”

“…The analysis is on the basis of the geographic distances between the wild-type and substituted amino acid residues in the three-dimensional model, according the method described earlier. [19][20][21][22]25 Structural modeling of the surface region affected by representative amino acid substitutions…”

Structural characterization of mutant α-galactosidases causing Fabry disease

“…The average ASA values of the residues for which a substitution had been found in the classic and variant Fabry groups were determined and compared with each other, as described previously Sugawara et al 2008).…”

Laronidase (Aldurazyme®): enzyme replacement therapy for mucopolysaccharidosis type I

“…Details regarding the pathophysiology of MPS-I remain to be elucidated. Impaired elastogenesis, postulated to be due to dermatan sulfate binding to and inactivation of elastin-binding protein, may be one factor [6] . The bone and joint changes associated with MPS-I are evident on radiographic examination as dysostosis multiplex (a constellation of bone changes, including gibbus deformity).…”