Structural modeling of mutant alpha-glucosidases resulting in a processing/transport defect in Pompe disease
| Autor: | Arnold J. J. Reuser, Kazuki Ohno, Seiji Saito, Masakazu Sekijima, Youichi Tajima, Kanako Sugawara, Hitoshi Sakuraba, Marian A. Kroos |
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| Přispěvatelé: | Molecular Genetics, Clinical Genetics |
| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Protein Conformation Mutant Molecular Sequence Data Endoplasmic Reticulum Protein structure SDG 3 - Good Health and Well-being Genetics Humans Homology modeling Amino Acid Sequence Peptide sequence Genetics (clinical) chemistry.chemical_classification Sequence Homology Amino Acid Glycogen Storage Disease Type II Endoplasmic reticulum alpha-Glucosidases Amino acid Transport protein Protein Transport Enzyme chemistry Biochemistry Amino Acid Substitution Mutant Proteins Lysosomes Protein Processing Post-Translational |
| Zdroj: | Journal of Human Genetics, 54(6), 324-330. Nature Publishing Group |
| ISSN: | 1434-5161 |
| Popis: | To elucidate the mechanism underlying transport and processing defects from the viewpoint of enzyme folding, we constructed three-dimensional models of human acid a-glucosidase encompassing 27 relevant amino acid substitutions by means of homology modeling. Then, we determined in each separate case the number of affected atoms, the root-mean-square distance value and the solvent-accessible surface area value. The analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid a-glucosidase. They were distributed from the core to the surface of the enzyme molecule, and the predicted structural changes varied from large to very small. Among the structural changes, we paid particular attention to G377R and G483R. These two substitutions are predicted to cause electrostatic changes in neighboring small regions on the molecular surface. The quality control system of the endoplasmic reticulum apparently detects these very small structural changes and degrades the mutant enzyme precursor (G377R), but also the cellular sorting system might be misled by these minor changes whereby the precursor is secreted instead of being transported to lysosomes (G483R). Journal of Human Genetics (2009) 54, 324-330; doi:10.1038/jhg.2009.32; published online 3 April 2009 |
| Databáze: | OpenAIRE |
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