| Autor: |
Balasundaram A; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India., Ramireddy S; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India., S UK; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India., D TK; Faculty of Allied Health Sciences, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India., Tayubi IA; Department of Computer Science, Faculty of Computing and Information Technology, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia., Zayed H; Department of Biomedical Sciences College of Health Sciences, QU Health, Qatar University, Doha, Qatar., C GPD; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India. |
| Abstrakt: |
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We utilized the PhosphoSitePlus tool to identify the AGA protein's phosphorylation sites. The phosphorylation was induced on the specific residue of the three-dimensional AGA protein, and the structural changes upon phosphorylation were studied via molecular dynamics simulation. Furthermore, the structural behaviour of C163S mutation and C163S mutation with adjacent phosphorylation was investigated. We have examined the structural impact of phosphorylated forms and C163S mutation in AGA. Molecular dynamics simulations (200 ns) exposed patterns of deviation, fluctuation, and change in compactness of Y178 phosphorylated AGA protein (Y178-p), T215 phosphorylated AGA protein (T215-p), T324 phosphorylated AGA protein (T324-p), C163S mutant AGA protein (C163S), and C163S mutation with Y178 phosphorylated AGA protein (C163S-Y178-p). Y178-p, T215-p, and C163S mutation demonstrated an increase in intramolecular hydrogen bonds, leading to greater compactness of the AGA forms. Principle component analysis (PCA) and Gibbs free energy of the phosphorylated/C163S mutation structures exhibit transition in motion/orientation than Wild type (WT). T215-p may be more dominant among these than the other studied phosphorylated forms. It might contribute to hydrolyzing L-asparagine functioning as an asparaginase, thereby regulating neurotransmitter activity. This study revealed structural insights into the phosphorylation of Y178, T215, and T324 in AGA protein. Additionally, it exposed the structural changes of the C163S mutation and C163S-Y178-p of AGA protein. This research will shed light on a better understanding of AGA's phosphorylated mechanism.Communicated by Ramaswamy H. Sarma. |
