Single‐walled tubulin ring polymers

Boukari, Hacène; Sackett, Dan L.; Schuck, Peter; Nossal, Ralph

doi:10.1002/bip.20752

Cited by 11 publications

(13 citation statements)

References 56 publications

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“…Such an inhibition could occur because stathmin's binding site is close to the interface between protofilaments (23-25). Alternatively, because both DL-rings and the T 2 S complex are curved (15)(16)(17)(18)26), stathmin could inhibit lateral interactions by inducing in protofilaments a degree of curvature that is incompatible with their incorporation into the lattice.…”

Section: Significancementioning

confidence: 99%

“…(ii) GMPCPP MTs (CPP-MT), which have a GTP lattice and some free protofilaments (13,14); these are made by replacing the standard GTP nucleotide with the slowly hydrolysable analog GMPCPP. In addition, we chose to study three more unusual conformations: (iii) GMPCPP protofilaments (CPP-PF), which are produced by treating GMPCPP MTs with calcium; the calcium decomposes many of the MTs into protofilaments, but also leaves sheets and MT-like structures (13,14); (iv) Dolastatin-10 rings (DL-rings), which are formed by adding the drug Dolastatin-10 to tubulin; these rings are structurally analogous to the curled protofilaments that form during depolymerization (15)(16)(17)(18); and (v) Zinc-induced tubulin sheets (Zn-sheets), which are made by adding ZnCl 2 , and are characterized by laterally associated protofilaments arranged in an antiparallel fashion, resulting in Zn-sheets having two protofilaments exposed at opposite edges (19,20). Finally, it has been noted that the ability of stathmin to sequester tubulin depends strongly on pH (4,6).…”

Section: Significancementioning

confidence: 99%

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Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin

Gupta¹,

Duan³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of microtubule dynamic instability is crucial for cellular processes, ranging from mitosis to membrane transport. Stathmin (also known as oncoprotein 18/Op18) is a prominent microtubule destabilizer that acts preferentially on microtubule minus ends. Stathmin has been studied intensively because of its association with multiple types of cancer, but its mechanism of action remains controversial. Two models have been proposed. One model is that stathmin promotes microtubule catastrophe indirectly, and does so by sequestering tubulin; the other holds that stathmin alters microtubule dynamics by directly destabilizing growing microtubules. Stathmin's sequestration activity is well established, but the mechanism of any direct action is mysterious because stathmin binds to microtubules very weakly. To address these issues, we have studied interactions between stathmin and varied tubulin polymers. We show that stathmin binds tightly to Dolastatin-10 tubulin rings, which mimic curved tubulin protofilaments, and that stathmin depolymerizes stabilized protofilament-rich polymers. These observations lead us to propose that stathmin promotes catastrophe by binding to and acting upon protofilaments exposed at the tips of growing microtubules. Moreover, we suggest that stathmin's minus-end preference results from interactions between stathmin's N terminus and the surface of α-tubulin that is exposed only at the minus end. Using computational modeling of microtubule dynamics, we show that these mechanisms could account for stathmin's observed activities in vitro, but that both the direct and sequestering activities are likely to be relevant in a cellular context. Taken together, our results suggest that stathmin can promote catastrophe by direct action on protofilament structure and interactions.Zn-sheets | GMPCPP | T 2 S complex | computer simulation

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin

Gupta¹,

Duan³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Second, they appear rigid and some are very stable, especially upon dilution down to nanomolar concentrations [4]. Third, under certain conditions, dolastatin-tubulin nanorings tend to aggregate into large structures, likely stacks of nanorings, as suggested from analysis of SANS data [3]. Red box shows a tubulin dimer.…”

Section: Introductionmentioning

confidence: 96%

“…Our ongoing activities have focused on an unusual class of water-soluble, freely-diffusing, biomacromolecular nanorings, formed from interactions of the protein heterodimer, -tubulin, and novel small peptides (e.g, cryptophycin and dolastatin) extracted from certain marine organisms (e.g cyanobacteria and shell-less mollusks) [2][3][4][5]. An example is shown in Figure 1, the 8-dimer ring of tubulin-cryptophycin [5].…”

Section: Introductionmentioning

confidence: 99%

“…Examples are microtubules (hollow cylinders, 25 nm diameter; the normal polymeric product of tubulin assembly) [1,6], double-walled nanorings [8], and single-walled tubulin nanorings [2][3][4][5] -the latter being the subject of this paper. Extensive work has been performed to characterize the atomic structure and the biochemical properties of tubulin and some of its biopolymeric structures with emphasis on answering specific biological questions such as protein trafficking and cell division [1].…”

Section: Introductionmentioning

confidence: 99%

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Tubulin Nanorings

Boukari

Sackett

2016

MRS Advances

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Biological systems routinely produce nanoscopic molecular structures with considerably less dispersion in size and shape than encountered in most manufactured materials. Indeed, Biological structures are frequently and essentially monodisperse. An example of this uniformity, combined with an intriguing geometry, is the nanometer-scale protein nanorings produced by interaction of the protein tubulin with certain hydrophobic tri-, tetra-and pentapeptides originally extracted as natural products from marine biosystems. Different peptides produce different sized nanorings, but we focus on those produced by binding to tubulin of the cyclic depsipeptide cryptophycin. The nanorings that form upon binding of this ligand show a sharp mass distribution indicating that the nanorings are made of 8 tubulin dimers of 100 kDa.In this submission, we demonstrate how a combination of fluorescence correlation spectroscopy, dynamic light scattering, electron microscopy, analytical ultracentrifugation, small-angle neutron scattering, and modeling is applied to reveal interactions of tubulin and cryptophycin in solution and to characterize their structures. We find that the cryptophycin-tubulin nanorings (~25 nm diameter) are single-walled, appear rigid, are composed of 8 tubulin dimers in a single closed ring, and are stable upon dilution to nanomolar concentrations.Similar studies with a different peptide, the linear pentapeptide dolastatin 10, demonstrated that binding of this peptide to tubulin produces larger nanorings (14 tubulin dimers, ~45 nm diameter rings), with slightly different properties. The ability to adjust the ring size with different peptides, and produce uniform nanorings with properties that differ slightly between size classes, makes the tubulin-peptide ring structures an appealing structural system.

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Drugs that target dynamic microtubules: A new molecular perspective

Stanton

Gernert

Nettles

et al. 2011

Medicinal Research Reviews

454

352

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Microtubules have long been considered an ideal target for anticancer drugs because of the essential role they play in mitosis, forming the dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Although these diverse molecules are known to affect microtubule dynamics upon binding to one of the three established drug domains (taxane, vinca alkaloid, or colchicine site), the exact mechanism by which each drug works is still an area of intense speculation and research. In this study, we review the effects of microtubule-binding chemotherapeutic agents from a new perspective, considering how their mode of binding induces conformational changes and alters biological function relative to the molecular vectors of microtubule assembly or disassembly. These “biological vectors” can thus be used as a spatiotemporal context to describe molecular mechanisms by which microtubule-targeting drugs work.

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Single‐walled tubulin ring polymers

Cited by 11 publications

References 56 publications

Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin

Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin

Tubulin Nanorings

Drugs that target dynamic microtubules: A new molecular perspective

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