A hereditary spastic paraplegia–associated atlastin variant exhibits defective allosteric coupling in the catalytic core

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 disor...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-01, Vol.293 (2), p.687-700
Main Authors: O’Donnell, John P., Byrnes, Laura J., Cooley, Richard B., Sondermann, Holger
Format: Article
Language:English
Subjects:
allosteric regulation
Animals
axonopathy
Catalytic Domain
dynamin-related proteins
enzyme structure
GTP Phosphohydrolases - metabolism
GTPase
Guanosine Triphosphate - metabolism
hereditary spastic paraplegia
Humans
membrane fusion
Membrane Fusion - genetics
Membrane Fusion - physiology
Protein Structure and Folding
Spastic Paraplegia, Hereditary - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA117.000380