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An Allosteric Network in Spastin Couples Multiple Activities Required for Microtubule Severing

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An Allosteric Network in Spastin Couples Multiple Activities Required for Microtubule Severing ARTICLES https://doi.org/10.1038/s41594-019-0257-3 An allosteric network in spastin couples multiple activities required for microtubule severing Colby R. Sandate 1, Agnieszka Szyk2, Elena A. Zehr2, Gabriel C. Lander 1* and Antonina Roll-Mecak 2,3* The AAA+ ATPase spastin remodels microtubule arrays through severing and its mutation is the most common cause of hered- itary 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 trans- locases into their active conformations. We show that this allosteric network is essential for severing and is a hotspot for HSP mutations. pastin is a microtubule-severing AAA ATPase (ATPases cooperative and requires ATP4. The substrate-dependent oligomer- associated with diverse cellular activities) whose function is ization is likely important for the specificity and timing of action of important in basic cell biological processes ranging from neu- these AAA+ ATPases in the cell, as unregulated spastin and katanin S 17–19 rogenesis and axonal maintenance to nuclear envelope breakdown, microtubule severing activity is highly deleterious . The majority vesicle trafficking, mitosis and cytokinesis1. Spastin is recruited to of disease-associated mutations of the SPAST gene are found in the endosomes and the midbody through its interaction with ESCRTIII ATPase domain of spastin. and is thought to participate in the coordinated remodeling of Microtubule severing by spastin requires the β-tubulin membranes and microtubules1. Spastin ATPase activity is stimu- C-terminal tail, an intrinsically disordered element that decorates lated by microtubules2–4 and microtubule severing activity requires the microtubule surface. While the α-tubulin tail contributes to adenosine triphosphate (ATP) hydrolysis2,5–7. Spastin mutations are binding, it is not required for severing activity20. It was proposed responsible for ~50% of hereditary spastic paraplegias (HSPs), a that microtubule severing involves the hexamerization of spastin large and clinically diverse family of neurodegenerative disorders8. protomers around the ~20 residue negatively charged tubulin tail, In the pure form of the disease, HSP patients typically exhibit axonal and the subsequent pulling of the tubulin subunit out of the micro- degeneration in motor axons of the corticospinal tract, leading to tubule lattice using ATP-driven conformational changes in three progressive lower limb spasticity and weakness8–10. Studies in model pore loops that help translocate the substrate through the central organisms11 and patient-derived induced pluripotent stem cells12 pore of the hexameric ATPase6,21. However, there has been no direct have shown that neurons are especially sensitive to spastin gene demonstration of the tubulin tail engagement by the spastin pore dosage. Cellular and biochemical studies have shown that many nor any atomistic structural information on the spastin hexamer of the disease-associated mutations examined impair microtubule or its interaction with the tubulin tail substrate. The interaction of severing and ATP hydrolysis5–7,13. However, the etiology of spastin spastin with the microtubule is strongly enhanced by the polyglu- induced HSP is still poorly understood. tamylation of the β-tubulin tail20, a post-translational modification Spastin has a modular structure comprising a three-helix bundle that involves the addition of multiple glutamate chains of variable microtubule-interacting and trafficking (MIT) domain, a poorly lengths; unmodified microtubules are not effectively severed at conserved linker region and an AAA+ ATPase domain. This in vivo spastin concentrations20,22. As many as 21 glutamates have domain architecture is shared among all three known microtu- been detected on tubulin tails in vivo23,24. Polyglutamylation is bule severing enzymes: spastin, katanin and fidgetin1. The ATPase highly abundant in neurons where spastin activity is required for domain is structurally homologous to that of other members of neurite extension as well as axonal maintenance and regeneration11. the AAA+ protein family and consists of an α/β nucleotide bind- Here, we present the cryo-EM structure of the spastin hexamer ing domain (NBD) and a four-helix bundle domain (HBD). Both in complex with a polyglutamate peptide at ~3.2 Å resolution. The spastin and katanin differ from other AAA+ ATPase enzymes in structure reveals an asymmetric hexamer with the AAA domains that they contain two additional helices within the NBD that are arranged in a split lock-washer conformation. Two conserved pore essential for severing6,14. The AAA+ ATPase domains hexamerize loops from the six protomers form a double-helical staircase grip- in a nucleotide-dependent manner and the tubulin substrate low- ping the odd and even glutamates of the substrate peptide, respec- ers the critical concentration for oligomerization15,16. Consistent tively. Residues in this double helix are positively charged and with this, high-affinity binding of spastin to microtubules is highly neutralize the electronegative polyglutamate peptide, consistent 1The Scripps Research Institute, La Jolla, CA, USA. 2Cell Biology and Biophysics Unit, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. 3Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, Bethesda, MD, USA. *e-mail: [email protected]; [email protected] NATURE STRUCTURAL & MOlecULAR BIOLOGY | VOL 26 | AUGUST 2019 | 671–678 | www.nature.com/nsmb 671 ARTICLES NATURE STRUCTURAL & MOLECULAR BIOLOGY with the regulation of microtubule severing by polyglutamylation Table 1 | Cryo-EM data collection, refinement and validation of tubulin tails. The substrate binding pore loops are allosterically statistics coupled to the ATP binding site as well as the oligomerization inter- faces, providing a structural explanation for the tubulin substrate SpastinE583Q binding-induced spastin activation. The majority of the residues in (EMD-20226, this allosteric network are mutated in HSP patients, underscoring PDB 6P07) their importance to spastin function. Our comprehensive structural analysis of all reported HSP-associated spastin missense mutations Data collection and processing in its AAA core provides a framework for understanding spastin Microscope Thermo Fischer Talos molecular dysfunction. Arctica Camera Gatan K2 Summit DED Results Magnification (nominal) ×36,000 Spastin forms a hexameric spiral. Unlike many AAA ATPases, + Magnification (calibrated) 43,478.3 spastin exists as a monomer or dimer in the absence of nucleotide or × bound to ADP, and only assembles into hexamers upon ATP bind- Voltage (kV) 200 ing3,6 This hexamer is labile and falls apart at lower concentrations6. Total electron exposure (e–/Å 2) 52 To stabilize the hexameric state for structural studies by cryo-elec- Exposure rate (e-/pixel/s) 5.6 tron microscopy (cryo-EM) we used a commonly used mutation in Defocus range (μm) −1.0 to −2.0 the Walker B motif of the ATPase domain (E583Q), which retains ATP binding but prevents ATP hydrolysis6,13. Analytical ultracen- Pixel size (Å) 1.15 trifugation (AUC) shows that this construct assembles into hex- Micrographs collected (no.) 2,534 amers in the presence of ATP at concentrations as low as 6 µM Micrographs used (no.) 2,534 (Supplementary Fig. 1a). Initial structure determination yielded a Total extracted particles (no.) 2,736,865 reconstruction of the spastin hexamer limited to ~3.8 Å resolution Refined particles (no.) 1,259,553 showing cryo-EM density of adventitious peptide binding. As poly- glutamylation enhances substrate binding20 and spastin has been Final particles (no.) 488,385 shown to interact with polyglutamate peptides, we incubated our Symmetry imposed C1 spastin preparation with polyglutamate (Methods). This increased Resolution (global) the proportion of intact hexamers and allowed structural determi- FSC 0.5 (unmasked/masked) 7.0/3.6 nation of the spastin-peptide complex to ~3.2 Å resolution (Table 1, Fig. 1 and Supplementary Figs. 2 and 3). Polyglutamate activates FSC 0.143 (unmasked/masked) 4.3/3.2 spastin ATPase with a maximal activation of approximately sixfold Resolution range (local) 3–5 above the basal level (Supplementary Fig. 1b), comparable to the Model composition 2 activation reported with microtubules . AUC with a fluorescently Nonhydrogen atoms 14,089 labeled polyglutamate peptide shows that it comigrates with the Protein residues 1804 spastin hexamer (Supplementary Fig. 1c). The choice of polyglu- tamate also overcomes the experimental issue of placing enzymes Ligands 12 in a specific register with respect to the tubulin tail sequence that is Refinement overrepresented in polyglutamates, but also contains other amino Initial model used (PDB code) 3B9P acid residues. Average FSC 3.2 The overall architecture of the spastin hexamer
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