The deleterious variants of N-acetylgalactosamine-6-sulfatase (GalN6S) enzyme trigger Morquio a syndrome by disrupting protein foldings

Abstract

Lysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.

Communicated by Ramaswamy H. Sarma

Keywords:

• GALNS gene
• galactosamine-6-sulfatase
• Morquio A syndrome
• nsSNPs
• molecular dynamics

Authors’ contributions

Conceptualization, Jiuyi Li and Yasir Ali; Data curation, Waqas Ahmad Khalid, Yasir Ali, and Hina Imtiaz; Formal analysis, Yasir Ali and Arif Mahmood; Funding acquisition, Lingkun Huang; Investigation, Yasir Ali, Fouzia Gul and Rimsha Yousaf; Methodology, Jiuyi Li, Yasir Ali, Fouzia Gul and Huiyin Deng; Resources, Lingkun Huang and Xiongwen Yang; Software, Yasir Ali and Xiongwen Yang and Arif Mahmood; Supervision, Saadullah Khattak; Validation, Yasir Ali; Visualization, Yasir Ali and Huiyin Deng; Writing—original draft, Jiuyi Li, Rimsha Yousaf, and Yasir Ali; Writing—review & editing, Yasir Ali and Saadullah Khattak; Investigation and resources, Abid Ali shah.

Data availability statement

Datasets analyzed or generated during the study supporting the reported results are included in the article.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This research received no external funding.