Large scale analysis of the mutational landscape in β-glucuronidase: A major player of mucopolysaccharidosis type VII.

Abstract

The lysosomal storage disorders are a group of 50 unique inherited diseases characterized by unseemly lipid storage in lysosomes. These malfunctions arise due to genetic mutations that result in deficiency or reduced activities of the lysosomal enzymes, which are responsible for catabolism of biological macromolecules. Sly syndrome or mucopolysaccharidosis type VII is a lysosomal storage disorder associated with the deficiency of β-glucuronidase (EC 3.2.1.31) that catalyzes the hydrolysis of β-D-glucuronic acid residues from the non-reducing terminal of glycosaminoglycan. The effects of the disease causing mutations on the framework of the sequences and structure of β-glucuronidase (GUSBp) were analyzed utilizing a variety of bioinformatic tools. These analyses showed that 211 mutations may result in alteration of the biological activity of GUSBp, including previously experimentally validated mutations. Finally, we refined 90 disease causing mutations, which presumably cause a significant impact on the structure, function, and stability of GUSBp. Stability analyses showed that mutations p.Phe208Pro, p.Phe539Gly, p.Leu622Gly, p.Ile499Gly and p.Ile586Gly caused the highest impact on GUSBp stability and function because of destabilization of the protein structure. Furthermore, structures of wild type and mutant GUSBp were subjected to molecular dynamics simulation to examine the relative structural behaviors in the explicit conditions of water. In a broader view, the use of in silico approaches provided a useful understanding of the effect of single point mutations on the structure-function relationship of GUSBp.

• Authors: Faez Iqbal Khan, Mohd Shahbaaz, Krishna Bisetty, Abdul Waheed, William S Sly, Faizan Ahmad, Md Imtaiyaz Hassan
• Journal: Gene (Gene) Vol. 576 Issue 1 Pt 1 Pg. 36-44 (Jan 15 2016) ISSN: 1879-0038 [Electronic] Netherlands
• PMID: 26415878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Glucuronidase

Topics

• Amino Acid Substitution
• Computer Simulation
• Glucuronidase (chemistry, genetics)
• Humans
• Molecular Dynamics Simulation
• Mucopolysaccharidosis VII (enzymology, genetics)
• Mutation, Missense
• Protein Structure, Tertiary
• Structure-Activity Relationship