A computational method to characterize the missense mutations in the catalytic domain of GAA protein causing Pompe disease.
Author | Thirumal Kumar, D |
Author | Umer Niazullah, Maryam |
Author | Tasneem, Sadia |
Author | Judith, E |
Author | Susmita, B |
Author | George Priya Doss, C |
Author | Selvarajan, E |
Author | Zayed, Hatem |
Available date | 2019-02-14T04:54:01Z |
Publication Date | 2019-03-01 |
Publication Name | Journal of Cellular Biochemistry |
Identifier | http://dx.doi.org/10.1002/jcb.27624 |
Citation | Thirumal Kumar D, Umer Niazullah M, Tasneem S, et al. A computational method to characterize the missense mutations in the catalytic domain of GAA protein causing Pompe disease. J Cell Biochem. 2019;120:3491‐3505. https://doi.org/10.1002/jcb.27624 |
ISSN | 0730-2312 |
Abstract | Pompe disease is an autosomal recessive lysosomal storage disease caused by acid α-glucosidase (GAA) deficiency, resulting in intralysosomal accumulation of glycogen, including cardiac, skeletal, and smooth muscle cells. The GAA gene is located on chromosome 17 (17q25.3), the GAA protein consists of 952 amino acids; of which 378 amino acids (347-726) falls within the catalytic domain of the protein and comprises of active sites (518 and 521) and binding sites (404, 600, 616, and 674). In this study, we used several computational tools to classify the missense mutations in the catalytic domain of GAA for their pathogenicity and stability. Eight missense mutations (R437C, G478R, N573H, Y575S, G605D, V642D, L705P, and L712P) were predicted to be pathogenic and destabilizing to the protein structure. These mutations were further subjected to phenotyping analysis using SNPeffect 4.0 to predict the chaperone binding sites and structural stability of the protein. The mutations R437C and G478R were found to compromise the chaperone-binding activity with GAA. Molecular docking analysis revealed that the G478R mutation to be more significant and hinders binding to the DNJ (Miglustat) compared with the R437C. Further molecular dynamic analysis for the two mutations demonstrated that the G478R mutation was acquired higher deviation, fluctuation, and lower compactness with decreased intramolecular hydrogen bonds compared to the mutant R437C. These data are expected to serve as a platform for drug design against Pompe disease and will serve as an ultimate tool for variant classification and interpretations. |
Language | en |
Publisher | Wiley |
Subject | GAA Pompe disease catalytic sites molecular docking molecular dynamics protein misfolding variant classification |
Type | Article |
Pagination | 3491-3505 |
Issue Number | 3 |
Volume Number | 120 |
ESSN | 1097-4644 |
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Biomedical Sciences [712 items ]