A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching
| العنوان: | A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching |
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| المؤلفون: | Kelly, Carolyn M., Zeiger, Peter J., Narayanan, Vinodh, Ramsey, Keri, Sondermann, Holger |
| المصدر: | The Journal of Biological Chemistry The journal of biological chemistry 298(1), 101438 (2022). doi:10.1016/j.jbc.2021.101438 |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Protein Conformation, membrane tethering, MLV, multilamellar vesicle, DRP, dynamin-related protein, FRET, Förster resonance energy transfer, HSN, hereditary sensory neuropathy, EEG, electroencephalogram, GTP Phosphohydrolases, ER, endoplasmic reticulum, GTP-Binding Proteins, Humans, ddc:610, CP, cerebral palsy, GED, GTPase effector domain, GTPase, HSP, hereditary spastic paraplegia, Spastic Paraplegia, Hereditary, BSE, bundle signaling element, Membrane Proteins, ATL1, atlastin-1, WT, wild-type, Mutagenesis, Insertional, TKO, triple-knockout, Mutation, ACTH, adrenocorticotropic hormone, neuropathy, MRI, magnetic resonance imaging, Research Article |
| الوصف: | JBC papers in press 298(1), 101438 (2021). doi:10.1016/j.jbc.2021.101438 Hereditary spastic paraplegia (HSP) comprises a heterogenous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 (ATL1), encoding a dynamin superfamily member which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), accounts for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations is crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant pre-hydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function. Published by American Soc. for Biochemistry and Molecular Biology, Bethesda, MD. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::19ae4587531d6d7ae408deb09c6a347e http://europepmc.org/articles/PMC8688574 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....19ae4587531d6d7ae408deb09c6a347e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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