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

K Sugawara, S Saito, M Sekijima, K Ohno, Y Tajima, Marian Haan, Arnold Reuser, H Sakuraba

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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
Original languageUndefined/Unknown
Pages (from-to)324-330
Number of pages7
JournalJournal of Human Genetics
Issue number6
Publication statusPublished - 2009

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  • EMC MGC-02-96-01

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