A previously undescribed tubulin binder

Field, Jessica J.; Waight, Andrew B.; Senter, Peter D.

doi:10.1073/pnas.1414572111

Cited by 18 publications

(13 citation statements)

References 22 publications

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“…Stabilizing agents, such as vinca alkaloids, induce assembly of heterodimers by increasing lateral protofilament interactions. Destabilizing agents, such as taxanes, reduce polymerization by inducing an altered conformation [ 139 ].…”

Section: Antiproliferative Effectsmentioning

confidence: 99%

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

et al. 2017

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Despite the huge investment into research and the significant effort and advances made in the search for new anticancer drugs in recent decades, cancer cure and treatment continue to be a formidable challenge. Many sources, including plants, animals, and minerals, have been explored in the oncological field because of the possibility of identifying novel molecular therapeutics. Marine sponges are a prolific source of secondary metabolites, a number of which showed intriguing tumor chemopreventive and chemotherapeutic properties. Recently, Food and Drug Administration-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin’s disease. The chemopreventive and potential anticancer activity of marine sponge-derived compounds could be explained by multiple cellular and molecular mechanisms, including DNA protection, cell-cycle modulation, apoptosis, and anti-inflammatory activities as well as their ability to chemosensitize cancer cells to traditional antiblastic chemotherapy. The present article aims to depict the multiple mechanisms involved in the chemopreventive and therapeutic effects of marine sponges and critically explore the limitations and challenges associated with the development of marine sponge-based anticancer strategy.

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Section: Antiproliferative Effectsmentioning

confidence: 99%

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

et al. 2017

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“…Tubulin is known primarily for its role in the cytoskeleton, where it is assembled into microtubules in which the exposed end is the β subunit. As a result, microtubule-targeting drugs (MTDs) used in chemotherapy bind exclusively to the β subunit (1). Until recently, any physiological role of unassembled, cytosol-solubilized dimeric tubulin remained unknown.…”

mentioning

confidence: 99%

Structural features and lipid binding domain of tubulin on biomimetic mitochondrial membranes

Hoogerheide

Noskov

Jacobs

et al. 2017

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

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Dimeric tubulin, an abundant water-soluble cytosolic protein known primarily for its role in the cytoskeleton, is routinely found to be associated with mitochondrial outer membranes, although the structure and physiological role of mitochondria-bound tubulin are still unknown. There is also no consensus on whether tubulin is a peripheral membrane protein or is integrated into the outer mitochondrial membrane. Here the results of five independent techniques-surface plasmon resonance, electrochemical impedance spectroscopy, bilayer overtone analysis, neutron reflectometry, and molecular dynamics simulations-suggest that α-tubulin's amphipathic helix H10 is responsible for peripheral binding of dimeric tubulin to biomimetic "mitochondrial" membranes in a manner that differentiates between the two primary lipid headgroups found in mitochondrial membranes, phosphatidylethanolamine and phosphatidylcholine. The identification of the tubulin dimer orientation and membrane-binding domain represents an essential step toward our understanding of the complex mechanisms by which tubulin interacts with integral proteins of the mitochondrial outer membrane and is important for the structure-inspired design of tubulin-targeting agents.

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“…In microtubules, dimeric tubulin is assembled in such a way that the exposed, growing end of the microtubule is always the β-subunit. As a result, microtubule-targeting drugs (MTDs) used in chemotherapies bind exclusively to the β-subunit [ 43 ]. Until recently, any physiological role of unassembled, cytosol-solubilized dimeric tubulin, other than to serve as the building block for microtubules, remained unknown.…”

Section: How Vdac Permeability Is Regulated By Tubulin and α-Synucleinmentioning

confidence: 99%

Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains

Rostovtseva

Bezrukov

Hoogerheide

2021

IJMS

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The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. Two otherwise unrelated cytosolic proteins, tubulin, and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC’s sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics—reduced metabolite flux and increased calcium flux—are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC.

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A previously undescribed tubulin binder

Cited by 18 publications

References 22 publications

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

Structural features and lipid binding domain of tubulin on biomimetic mitochondrial membranes

Regulation of Mitochondrial Respiration by VDAC Is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains

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