National Institutes of Health/Office of the Director
DP2EB020402
United States
National Institutes of Health/Office of the Director
S10OD021634
United States
Citation
Journal: Nat Struct Mol Biol / Year: 2019 Title: An allosteric network in spastin couples multiple activities required for microtubule severing. Authors: Colby R Sandate / Agnieszka Szyk / Elena A Zehr / Gabriel C Lander / Antonina Roll-Mecak / Abstract: The AAA+ ATPase spastin remodels microtubule arrays through severing and its mutation is the most common cause of hereditary spastic paraplegias (HSP). Polyglutamylation of the tubulin C-terminal ...The AAA+ ATPase spastin remodels microtubule arrays through severing and its mutation is the most common cause of hereditary spastic paraplegias (HSP). Polyglutamylation of the tubulin C-terminal tail recruits spastin to microtubules and modulates severing activity. Here, we present a ~3.2 Å resolution cryo-EM structure of the Drosophila melanogaster spastin hexamer with a polyglutamate peptide bound in its central pore. Two electropositive loops arranged in a double-helical staircase coordinate the substrate sidechains. The structure reveals how concurrent nucleotide and substrate binding organizes the conserved spastin pore loops into an ordered network that is allosterically coupled to oligomerization, and suggests how tubulin tail engagement activates spastin for microtubule disassembly. This allosteric coupling may apply generally in organizing AAA+ protein translocases into their active conformations. We show that this allosteric network is essential for severing and is a hotspot for HSP mutations.
History
Deposition
May 16, 2019
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Header (metadata) release
Jun 12, 2019
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Map release
Jun 12, 2019
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Update
Mar 20, 2024
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Current status
Mar 20, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: Talos Arctica / Image courtesy: FEI Company
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Image processing
Details
Collected in counting mode, 48 frames movie-1, exposure time 12 s (250 ms frames), exposure rate of ~5.6 e- pixel-1 s-1, total exposure of ~52 e- angstrom-2 (1.08 e- angstrom-2 frame-1).
Particle selection
Number selected: 2736865 / Details: Template-picked particles
Startup model
Type of model: OTHER Details: An ab initio model generated from ~1.26 million template-picked particles cryoSPARC was used as a startup model.
Final reconstruction
Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 488385
Initial angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
Final angle assignment
Type: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
FSC plot (resolution estimation)
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