title: Structural consequences of amino acid substitutions causing Tay-Sachs disease.
abstract: To determine the structural changes in the alpha-subunit of beta-hexosaminidase due to amino acid substitutions causing Tay-Sachs disease, we built structural models of mutant alpha-subunits resulting from 33 missense mutations (24 infantile and 9 late-onset), and analyzed the influence of each amino acid replacement on the structure by calculating the number of atoms affected and determining the solvent-accessible surface area of the corresponding amino acid residue in the wild-type alpha-subunit. In the infantile Tay-Sachs group, the number of atoms influenced by a mutation was generally larger than that in the late-onset Tay-Sachs group in both the main chain and the side chain, and residues associated with the mutations found in the infantile Tay-Sachs group tended to be less solvent-accessible than those in the late-onset Tay-Sachs group. Furthermore, color imaging determined the distribution and degree of the structural changes caused by representative amino acid substitutions, and that there were also differences between the infantile and late-onset Tay-Sachs disease groups. Structural study is useful for elucidating the basis of Tay-Sachs disease.
authors.affiliation: Center for Biological Resources and Informatics, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Sugawara
authors.affiliation: Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan; Japan Science and Technology Agency, CREST, Kawaguchi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D005260:Female; D054818:Hexosaminidase A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D013661:Tay-Sachs Disease / Q000201:enzymology* / Q000235:genetics*
chemical_list: D054818:Hexosaminidase A