Abstract
To elucidate the basis of mucopolysaccharidosis type I (MPS I), we constructed structural models of mutant α-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-mean-square 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.
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Acknowledgments
We thank Dr. J. Ponder (Department of Biochemistry and Molecular Biophysics, Washington University) for providing us with the TINKER software. We also thank I.K. McDonald, D. Naylor, D. Jones, J.M. Thornton, S. Hubbard, D.K. Smith, R. Laskowski, and G. Hutchinson for providing us with the HBPLUS. This work was partly supported by grants from the Japan Society for the Promotion of Science, the Ministry of Education, Science, Sports and Culture of Japan, the Ministry of Health and Welfare of Japan, the Japan Science and Technology Agency, and CREST.
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Sugawara, K., Saito, S., Ohno, K. et al. Structural study on mutant α-l-iduronidases: insight into mucopolysaccharidosis type I. J Hum Genet 53, 467–474 (2008). https://doi.org/10.1007/s10038-008-0272-4
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DOI: https://doi.org/10.1007/s10038-008-0272-4
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