7OL3

Human ATL1 N417ins (catalytic core)

7OL3 の概要

• エントリーDOI: 10.2210/pdb7ol3/pdb
• 分子名称: Atlastin-1, GUANOSINE-5'-DIPHOSPHATE, TETRAFLUOROALUMINATE ION, ... (5 entities in total)
• 機能のキーワード: dynamin-related protein, membrane fusion, endoplasmic reticulum, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106371.93

構造登録者

Kelly, C.M.,Sondermann, H. (登録日: 2021-05-19, 公開日: 2021-07-21, 最終更新日: 2024-01-31)

主引用文献

Kelly, C.M.,Zeiger, P.J.,Narayanan, V.,Ramsey, K.,Sondermann, H.
A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching.
J.Biol.Chem., 298:101438-101438, 2021

PubMed Abstract: Hereditary spastic paraplegia (HSP) comprises a heterogeneous 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), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are 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 prehydrolysis 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.

PubMed: 34808209
DOI: 10.1016/j.jbc.2021.101438

実験手法

X-RAY DIFFRACTION (1.9 Å)