A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core
| Autor: | John P. O’Donnell, Richard B. Cooley, Holger Sondermann, Laura J. Byrnes |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Atlastin Hereditary spastic paraplegia Allosteric regulation Mutant GTPase Biochemistry Membrane Fusion GTP Phosphohydrolases 03 medical and health sciences Catalytic Domain medicine Animals Humans Molecular Biology Chemistry Spastic Paraplegia Hereditary Endoplasmic reticulum Lipid bilayer fusion Cell Biology medicine.disease Enzyme structure Cell biology 030104 developmental biology Protein Structure and Folding Guanosine Triphosphate |
| Zdroj: | The Journal of biological chemistry. 293(2) |
| ISSN: | 1083-351X |
| Popis: | The dynamin-related GTPase atlastin (ATL) catalyzes membrane fusion of the endoplasmic reticulum and thus establishes a network of branched membrane tubules. When ATL function is compromised, the morphology of the endoplasmic reticulum deteriorates, and these defects can result in neurological disorders such as hereditary spastic paraplegia and hereditary sensory neuropathy. ATLs harness the energy of GTP hydrolysis to initiate a series of conformational changes that enable homodimerization and subsequent membrane fusion. Disease-associated amino acid substitutions cluster in regions adjacent to ATL's catalytic site, but the consequences for the GTPase's molecular mechanism are often poorly understood. Here, we elucidate structural and functional defects of an atypical hereditary spastic paraplegia mutant, ATL1-F151S, that is impaired in its nucleotide-hydrolysis cycle but can still adopt a high-affinity homodimer when bound to a transition-state analog. Crystal structures of mutant proteins yielded models of the monomeric pre- and post-hydrolysis states of ATL. Together, these findings define a mechanism for allosteric coupling in which Phe151 is the central residue in a hydrophobic interaction network connecting the active site to an interdomain interface responsible for nucleotide loading. |
| Databáze: | OpenAIRE |
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