A computational method to characterize the missense mutations in the catalytic domain of GAA protein causing Pompe disease. Issue 3 (3rd October 2018)

• Record Type: Journal Article
• Authors: Thirumal Kumar, D; Umer Niazullah, Maryam; Tasneem, Sadia; Judith, E; Susmita, B; George Priya Doss, C; Selvarajan, E; Zayed, Hatem
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 3(2019)
• Page Start: 3491
• Page End: 3505
• Publication Date: 2018-10-03
• Subjects: catalytic sites -- GAA -- molecular docking -- molecular dynamics -- Pompe disease -- protein misfolding -- variant classification; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27624
• Languages: English
• ISSNs: 0730-2312

Abstract

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. Abstract : Domain‐wise three‐dimension structure of GAA protein.