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

ABSTRACT: 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.

SUBMITTER: Bhattacharyya T

PROVIDER: S-EPMC10123148 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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

Bhattacharyya Teerna T Ghosh Avishek A Verma Shailya S Raghu Padinjat P Sowdhamini Ramanathan R

Current research in structural biology 20230322

Myotubularin or MTM1 is a lipid phosphatase that regulates vesicular trafficking in the cell. The <i>MTM1</i> 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 ...[more]

PMID: 37101954

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Project description:BackgroundMutation(s) in proteins are a natural byproduct of evolution but can also cause serious diseases. Aminoacyl-tRNA synthetases (aaRSs) are indispensable components of all cellular protein translational machineries, and in humans they drive translation in both cytoplasm and mitochondria. Mutations in aaRSs have been implicated in a plethora of diseases including neurological conditions, metabolic disorders and cancer.ResultsWe have developed an algorithmic approach for genome-wide analyses of sequence substitutions that combines evolutionary, structural and functional information. This pipeline enabled us to super-annotate human aaRS mutations and analyze their linkage to health disorders. Our data suggest that in some but not all cases, aaRS mutations occur in functional and structural sectors where they can manifest their pathological effects by altering enzyme activity or causing structural instability. Further, mutations appear in both solvent exposed and buried regions of aaRSs indicating that these alterations could lead to dysfunctional enzymes resulting in abnormal protein translation routines by affecting inter-molecular interactions or by disruption of non-bonded interactions. Overall, the prevalence of mutations is much higher in mitochondrial aaRSs, and the two most often mutated aaRSs are mitochondrial glutamyl-tRNA synthetase and dual localized glycyl-tRNA synthetase. Out of 63 mutations annotated in this work, only 12 (~20%) were observed in regions that could directly affect aminoacylation activity via either binding to ATP/amino-acid, tRNA or by involvement in dimerization. Mutations in structural cores or at potential biomolecular interfaces account for ~55% mutations while remaining mutations (~25%) remain structurally un-annotated.ConclusionThis work provides a comprehensive structural framework within which most defective human aaRSs have been structurally analyzed. The methodology described here could be employed to annotate mutations in other protein families in a high-throughput manner.

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

Publications

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

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