Structural rationale to understand the effect of disease-associated mutations on Myotubularin

• Published in: Current research in structural biology 2023-01, Vol.5, p.100100, Article 100100
• Main Authors: Bhattacharyya, Teerna, Ghosh, Avishek, Verma, Shailya, Raghu, Padinjat, Sowdhamini, Ramanathan
• Format: Article
• Language: English
• Subjects: Ligand binding; Myotubular myopathy; Patient mutations; Phosphatase; Protein-ligand interactions
• ISSN: 2665-928X; 2665-928X
• DOI: 10.1016/j.crstbi.2023.100100

Myotubularin or MTM1 is a lipid phosphatase that regulates vesicular trafficking in the cell. The MTM1 gene is mutated in a severe form of muscular disease, X-linked myotubular myopathy or XLMTM, affecting 1 in 50,000 newborn males worldwide. There have been several studies on the disease pathology of XLMTM, but the structural effects of missense mutations of MTM1 are underexplored due to the unavailability of a crystal structure. MTM1 consists of three domains-a lipid-binding N-terminal GRAM domain, the phosphatase domain and a coiled-coil domain which aids dimerisation of Myotubularin homologs. While most mutations reported to date map to the phosphatase domain of MTM1, the other two domains on the sequence are also frequently mutated in XLMTM. To understand the overall structural and functional effects of missense mutations on MTM1, we curated several missense mutations and performed in silico and in vitro studies. Apart from significantly impaired binding to substrate, abrogation of phosphatase activity was observed for a few mutants. Possible long-range effects of mutations from non-catalytic domains on phosphatase activity were observed as well. Coiled-coil domain mutants have been characterised here for the first time in XLMTM literature. [Display omitted] •X-linked myotubular myopathy patient-derived mutations were mapped on lipid phosphatase domain of MTM1 subsequent to three-dimensional modelling.•Docking studies reveal long-range effects of mutations on MTM1 structure and substrate-binding capacities.•Most patient-derived mutations of MTM1 express poorly.•Several mutants of MTM1 show complete loss of phosphatase activity.•Combined approach using computational and experimental techniques to study molecular-level effects of mutations on MTM1 lipid phosphatase.