Crystal structure of the human spastin AAA domain

Taylor, Jennifer L.; White, Susan Roehl; Lauring, Brett; Kull, F. Jon

doi:10.1016/j.jsb.2012.03.002

Cited by 20 publications

(37 citation statements)

References 24 publications

(43 reference statements)

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“…To gain further insight into spastin oligomerization, we determined the crystal structure of human spastin in the apo state (Table ). Similar to the result of a previous structural study of human spastin , only the AAA domain was visible in the electron density, while the MTBD region was not visible. However, in the spastin AAA domain structure we determined, the loop linking helix α5 and β4 in the large subdomain and the short helix α9a between helices α9 and α10 in the small subdomain are better structured (Fig.…”

Section: Resultssupporting

confidence: 86%

The AAA protein spastin possesses two levels of basal ATPase activity

et al. 2018

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The AAA ATPase spastin is a microtubule-severing enzyme that plays important roles in various cellular events including axon regeneration. Herein, we found that the basal ATPase activity of spastin is negatively regulated by spastin concentration. By determining a spastin crystal structure, we demonstrate the necessity of intersubunit interactions between spastin AAA domains. Neutralization of the positive charges in the microtubule-binding domain (MTBD) of spastin dramatically decreases the ATPase activity at low concentration, although the ATP-hydrolyzing potential is not affected. These results demonstrate that, in addition to the AAA domain, the MTBD region of spastin is also involved in regulating ATPase activity, making interactions between spastin protomers more complicated than expected.

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Section: Resultssupporting

confidence: 86%

The AAA protein spastin possesses two levels of basal ATPase activity

et al. 2018

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“…In this study, the microtubules were severed into small fragments by spastin and spastin ΔN1 . This finding indicated that the function of spastin was closely related to the MTBD domain and AAA domain, which was consistent with the finding of a previous report (Taylor et al ., ). Among the AAA protein family members, spastin can bind to the microtubule via the MTBD domain and disrupt the fence‐like structure of microtubules by AAA ATPase.…”

Section: Discussionmentioning

confidence: 97%

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics

Zhang²,

Chen

et al. 2018

Developmental Neurobiology

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Changing the microtubule dynamics is sufficient to alter the axon and dendrite specification and development. Spastin participates in the growth and regeneration of neurites by severing microtubules into small segments, and collapsin response mediator protein 5 (CRMP5) provides structural support and serves as a track for cargo transport by promoting microtubule polymerization. Nevertheless, how spastin and CRMP5 cooperate to regulate neurite outgrowth by controlling the microtubule dynamics needs to be elucidated. In our present study, spastin interacted with CRMP5 in vitro and in vivo. The binding domains for the spastin and CRMP5 interaction were the N‐terminal fragment of spastin (residues 270–328) and the C‐terminal fragment of CRMP5 (residues 472–564). Spastin and its truncation mutants, including the microtubule‐binding domain (MTBD) and ATPases associated with diverse cellular activities (AAA) domain, were necessary for the severing of microtubules. Furthermore, we demonstrated that microtubule polymerization of CRMP5 interfered with the microtubule‐severing function of spastin. Knocking down either spastin or CRMP5 inhibited neurite outgrowth in hippocampal neurons. However, co‐transfected spastin and CRMP5 promoted the outgrowth of neurites including dendrites and axons. Taken together, our data support a model in which the spastin interaction with CRMP5 promotes neurite outgrowth by controlling the microtubule dynamics.

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“…Crystal structures of human, yeast and archaeal Vps4 24; 104; 105; 106; 107 , human and D. melanogaster Spastin 108; 109 , and C. elegans Fidgetin-like protein 1 (FIGL-1) 110 , have revealed details of the domain structure (Figure 4). The large AAA ATPase domain contains 5 α-helices that are arranged on either side of a central 5-stranded parallel β-sheet.…”

Section: Aaa Atpase Cassettementioning

confidence: 99%

“…Crystal structures of (a) human VPS4B (PDB ID: 1XWI) 24 , (b) human spastin (PDB ID: 3VFD) 109 and (c) human fidgetin-like 1 (FIGL-1, PDB ID: 3D8B) 110 . Coloring is as in Figure 1.…”

Section: Figurementioning

confidence: 99%

Meiotic Clade AAA ATPases: Protein Polymer Disassembly Machines

Monroe

Hill

2016

Journal of Molecular Biology

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Meiotic clade AAA ATPases, which were initially grouped on the basis of phylogenetic classification of their AAA ATPase cassette, include four relatively well characterized family members, Vps4, spastin, katanin, and fidgetin. These enzymes all function to disassemble specific polymeric protein structures, with Vps4 disassembling the ESCRT-III polymers that are central to the many membrane-remodeling activities of the ESCRT pathway, and spastin, katanin p60 and fidgetin affecting multiple aspects of cellular dynamics by severing microtubules. They share a common domain architecture that features an N-terminal MIT domain followed by a single AAA ATPase cassette. Meiotic clade AAA ATPases function as hexamers that can cycle between the active assembly and inactive monomers/dimers in a regulated process, and appear to disassemble their polymeric substrates by translocating subunits through the central pore of their hexameric ring. Recent studies with Vps4 have shown that nucleotide-induced asymmetry is a requirement for substrate binding to the pore loops, and that recruitment to the protein lattice via MIT domains also relieves auto-inhibition and primes the AAA ATPase cassettes for substrate binding. The most striking, unifying feature of meiotic clade AAA ATPases may be their MIT domain, which is a module that is found in a wide variety of proteins that localize to ESCRT-III polymers. Spastin also displays an adjacent microtubule-binding sequence, and the presence of both ESCRT-III and microtubule binding elements may underlie the recent findings that the ESCRT-III disassembly function of Vps4 and the microtubule-severing function of spastin, and potentially katanin and fidgetin, are highly coordinated.

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Crystal structure of the human spastin AAA domain

Cited by 20 publications

References 24 publications

The AAA protein spastin possesses two levels of basal ATPase activity

The AAA protein spastin possesses two levels of basal ATPase activity

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics

Meiotic Clade AAA ATPases: Protein Polymer Disassembly Machines

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