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Regulatory Mechanisms of Tubulin-Like Proteins

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 44310

Special Issue Editors

Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain
Interests: cancer; antibiotics; tubulin pharmacology; microtubule structure; FtsZ
Department of Structural and Chemical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain
Interests: tubulin; FtsZ; TubZ; microtubules; tubulin-like GTPases assembly; structural biology; cell division; DNA segregation

Special Issue Information

Dear Colleagues,

Proteins from the tubulin superfamily of GTPases are key in different biological processes such as DNA segregation, cell division and motility, and as cellular cytoskeletal components. They spread among eukaryotes, prokaryotes, plasmids and viruses and share two important features: A common 3D fold and the ability to assemble into dynamic filaments. The most well-known members of this family are tubulin and FtsZ, which are crucial in eukaryotic and prokaryotic cells division through their assembly into microtubules and protofilaments, respectively. Both filaments require a fine regulation for an accurate function and, hence, there are many partner proteins that help during the initial assembly steps, on the stabilization of the polymerized filaments or contributing to their disassembly. Importantly, these proteins are also crucial targets on the development of new antitumoral and antibiotic drugs due to their implication on cell division. In fact, many of these compounds binds to protein pockets or regions often involve on the interaction with protein partners and have shown a mechanism of action closely similar to those.

This Special Issue of IJMS aims to provide the current state-of-the-art in the regulatory mechanism of tubulin-like proteins through the interaction of, either, partner proteins or natural or synthetic compounds. We are seeking for original research papers and review articles related to this aspect of tubulin and tubulin-like proteins functioning.

Prof. José Fernando Díaz
Dr. María Ángela Oliva
Guest Editors

Manuscript Submission Information

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Keywords

  • Tubulin
  • FtsZ
  • Tubulin-like GTPases
  • Microtubule-associated proteins
  • FtsZ binding proteins
  • Microtubule binding agents
  • Antitumorals discovery
  • Antibacterial discovery
  • Antibiotics targeting FtsZ
  • TubZ
  • CetZ
  • Organelles FtsZ-like proteins

Published Papers (10 papers)

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Research

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12 pages, 5896 KiB  
Article
Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau
by Hyeanjeong Jeong, Seulgi Shin, Jun-Seok Lee, Soo Hyun Lee, Ja-Hyun Baik, Sungsu Lim and Yun Kyung Kim
Int. J. Mol. Sci. 2019, 20(17), 4283; https://doi.org/10.3390/ijms20174283 - 01 Sep 2019
Cited by 11 | Viewed by 4168
Abstract
Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer’s disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse [...] Read more.
Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer’s disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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13 pages, 4065 KiB  
Article
Surface Orientation and Binding Strength Modulate Shape of FtsZ on Lipid Surfaces
by Ileana Márquez, Gabriel Díaz-Haro and Marisela Vélez
Int. J. Mol. Sci. 2019, 20(10), 2545; https://doi.org/10.3390/ijms20102545 - 24 May 2019
Cited by 6 | Viewed by 2322
Abstract
We have used a simple model system to test the prediction that surface attachment strength of filaments presenting a torsion would affect their shape and properties. FtsZ from E. coli containing one cysteine in position 2 was covalently attached to a lipid bilayer [...] Read more.
We have used a simple model system to test the prediction that surface attachment strength of filaments presenting a torsion would affect their shape and properties. FtsZ from E. coli containing one cysteine in position 2 was covalently attached to a lipid bilayer containing maleimide lipids either in their head group (to simulate tight attachment) or at the end of a polyethylene glycol molecule attached to the head group (to simulate loose binding). We found that filaments tightly attached grew straight, growing from both ends, until they formed a two-dimensional lattice. Further monomer additions to their sides generated a dense layer of oriented filaments that fully covered the lipid membrane. After this point the surface became unstable and the bilayer detached from the surface. Filaments with a loose binding were initially curved and later evolved into straight thicker bundles that destabilized the membrane after reaching a certain surface density. Previously described theoretical models of FtsZ filament assembly on surfaces that include lateral interactions, spontaneous curvature, torsion, anchoring to the membrane, relative geometry of the surface and the filament ‘living-polymer’ condition in the presence of guanosine triphosphate (GTP) can offer some clues about the driving forces inducing these filament rearrangements. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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26 pages, 4144 KiB  
Article
A Survey on Tubulin and Arginine Methyltransferase Families Sheds Light on P. lividus Embryo as Model System for Antiproliferative Drug Development
by Maria Antonietta Ragusa, Aldo Nicosia, Salvatore Costa, Caterina Casano and Fabrizio Gianguzza
Int. J. Mol. Sci. 2019, 20(9), 2136; https://doi.org/10.3390/ijms20092136 - 30 Apr 2019
Cited by 5 | Viewed by 3339
Abstract
Tubulins and microtubules (MTs) represent targets for taxane-based chemotherapy. To date, several lines of evidence suggest that effectiveness of compounds binding tubulin often relies on different post-translational modifications on tubulins. Among them, methylation was recently associated to drug resistance mechanisms impairing taxanes binding. [...] Read more.
Tubulins and microtubules (MTs) represent targets for taxane-based chemotherapy. To date, several lines of evidence suggest that effectiveness of compounds binding tubulin often relies on different post-translational modifications on tubulins. Among them, methylation was recently associated to drug resistance mechanisms impairing taxanes binding. The sea urchin is recognized as a research model in several fields including fertilization, embryo development and toxicology. To date, some α- and β-tubulin genes have been identified in P. lividus, while no data are available in echinoderms for arginine methyl transferases (PRMT). To evaluate the exploiting of the sea urchin embryo in the field of antiproliferative drug development, we carried out a survey of the expressed α- and β-tubulin gene sets, together with a comprehensive analysis of the PRMT gene family and of the methylable arginine residues in P. lividus tubulins. Because of their specificities, the sea urchin embryo may represent an interesting tool for dissecting mechanisms of tubulin targeting drug action. Therefore, results herein reported provide evidences supporting the P. lividus embryo as animal system for testing antiproliferative drugs. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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17 pages, 2991 KiB  
Article
Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
by Francisco de Asís Balaguer, Tobias Mühlethaler, Juan Estévez-Gallego, Enrique Calvo, Juan Francisco Giménez-Abián, April L. Risinger, Erik J. Sorensen, Christopher D. Vanderwal, Karl-Heinz Altmann, Susan L. Mooberry, Michel O. Steinmetz, María Ángela Oliva, Andrea E. Prota and J. Fernando Díaz
Int. J. Mol. Sci. 2019, 20(6), 1392; https://doi.org/10.3390/ijms20061392 - 20 Mar 2019
Cited by 21 | Viewed by 4500
Abstract
It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent [...] Read more.
It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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19 pages, 1437 KiB  
Article
Synthesis, Microtubule-Binding Affinity, and Antiproliferative Activity of New Epothilone Analogs and of an EGFR-Targeted Epothilone-Peptide Conjugate
by Fabienne Zdenka Gaugaz, Andrea Chicca, Mariano Redondo-Horcajo, Isabel Barasoain, J. Fernando Díaz and Karl-Heinz Altmann
Int. J. Mol. Sci. 2019, 20(5), 1113; https://doi.org/10.3390/ijms20051113 - 05 Mar 2019
Cited by 4 | Viewed by 3466
Abstract
A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal [...] Read more.
A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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20 pages, 1743 KiB  
Article
Mapping the Contact Sites of the Escherichia coli Division-Initiating Proteins FtsZ and ZapA by BAMG Cross-Linking and Site-Directed Mutagenesis
by Winfried Roseboom, Madhvi G. Nazir, Nils Y. Meiresonne, Tamimount Mohammadi, Jolanda Verheul, Hansuk Buncherd, Alexandre M. J. J. Bonvin, Leo J. De Koning, Chris G. De Koster, Luitzen De Jong and Tanneke Den Blaauwen
Int. J. Mol. Sci. 2018, 19(10), 2928; https://doi.org/10.3390/ijms19102928 - 26 Sep 2018
Cited by 10 | Viewed by 3766
Abstract
Cell division in bacteria is initiated by the polymerization of FtsZ at midcell in a ring-like structure called the Z-ring. ZapA and other proteins assist Z-ring formation and ZapA binds ZapB, which senses the presence of the nucleoids. The FtsZ–ZapA binding interface was [...] Read more.
Cell division in bacteria is initiated by the polymerization of FtsZ at midcell in a ring-like structure called the Z-ring. ZapA and other proteins assist Z-ring formation and ZapA binds ZapB, which senses the presence of the nucleoids. The FtsZ–ZapA binding interface was analyzed by chemical cross-linking mass spectrometry (CXMS) under in vitro FtsZ-polymerizing conditions in the presence of GTP. Amino acids residue K42 from ZapA was cross-linked to amino acid residues K51 and K66 from FtsZ, close to the interphase between FtsZ molecules in protofilaments. Five different cross-links confirmed the tetrameric structure of ZapA. A number of FtsZ cross-links suggests that its C-terminal domain of 55 residues, thought to be largely disordered, has a limited freedom to move in space. Site-directed mutagenesis of ZapA reveals an interaction site in the globular head of the protein close to K42. Using the information on the cross-links and the mutants that lost the ability to interact with FtsZ, a model of the FtsZ protofilament–ZapA tetramer complex was obtained by information-driven docking with the HADDOCK2.2 webserver. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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Review

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13 pages, 2886 KiB  
Review
Tubulin in Platelets: When the Shape Matters
by Ernesto José Cuenca-Zamora, Francisca Ferrer-Marín, José Rivera and Raúl Teruel-Montoya
Int. J. Mol. Sci. 2019, 20(14), 3484; https://doi.org/10.3390/ijms20143484 - 16 Jul 2019
Cited by 39 | Viewed by 5464 | Correction
Abstract
Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating [...] Read more.
Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating platelets is stable and, under resting conditions, they maintain their typical discoid shape thanks to cytoskeleton proteins. The activation of platelets is associated with dynamic and rapid changes in the cytoskeleton. Two cytoskeletal polymer systems exist in megakaryocytes and platelets: actin filaments and microtubules, based on actin, and α- and β-tubulin heterodimers, respectively. Herein, we will focus on platelet-specific tubulins and their alterations and role of the microtubules skeleton in platelet formation (thrombopoiesis). During this process, microtubules mediate elongation of the megakaryocyte extensions (proplatelet) and granule trafficking from megakaryocytes to nascent platelets. In platelets, microtubules form a subcortical ring, the so-called marginal band, which confers the typical platelet discoid shape and is also responsible for changes in platelet morphology upon activation. Molecular alterations in the gene encoding β1 tubulin and microtubules post-translational modifications may result in quantitative or qualitative changes in tubulin, leading to altered cytoskeleton reorganization that may induce changes in the platelet number (thrombocytopenia), morphology or function. Consequently, β1-tubulin modifications may participate in pathological and physiological processes, such as development. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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14 pages, 2036 KiB  
Review
The Potential of Combining Tubulin-Targeting Anticancer Therapeutics and Immune Therapy
by Alexis Fong, Amanda Durkin and Hoyun Lee
Int. J. Mol. Sci. 2019, 20(3), 586; https://doi.org/10.3390/ijms20030586 - 30 Jan 2019
Cited by 34 | Viewed by 10362
Abstract
Cancer immune therapy has recently shown tremendous promise to combat many different cancers. The microtubule is a well-defined and very effective cancer therapeutic target. Interestingly, several lines of evidence now suggest that microtubules are intimately connected to the body’s immune responses. This raises [...] Read more.
Cancer immune therapy has recently shown tremendous promise to combat many different cancers. The microtubule is a well-defined and very effective cancer therapeutic target. Interestingly, several lines of evidence now suggest that microtubules are intimately connected to the body’s immune responses. This raises the possibility that the combination of microtubule inhibitors and immune therapy can be a highly effective option for cancer treatments. However, our understanding on this potentially important aspect is still very limited, due in part to the multifaceted nature of microtubule functions. Microtubules are not only involved in maintaining cell morphology, but also a variety of cellular processes, including the movement of secretory vesicles and organelles, intracellular macromolecular assembly, signaling pathways, and cell division. Microtubule inhibitors may be subdivided into two classes: Anti-depolymerization agents such as the taxane family, and anti-polymerization agents such as colchicine and vinka alkaloids. These two different classes may have different effects on immune cell subtypes. Anti-depolymerization agents can not only induce NK cells, but also appear to inhibit T regulatory (Treg) cells. However, different inhibitors may have different functions even among the same class. For example, the doxetaxel anti-depolymerization agent up-regulates cytotoxic T cells, while paclitaxel down-regulates them. Certain anti-polymerization agents such as colchicine appear to down-regulate most immune cell types, while inducing dendritic cell maturation and increasing M1 macrophage population. In contrast, the vinblastine anti-polymerization agent activates many of these cell types, albeit down-regulating Treg cells. In this review, we focus on the various effects of tubulin inhibitors on the activities of the body’s immune system, in the hope of paving the way to develop an effective cancer therapy by combining tubulin-targeting anticancer agents and immune therapy. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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13 pages, 2481 KiB  
Review
γ-Tubulin–γ-Tubulin Interactions as the Basis for the Formation of a Meshwork
by Catalina Ana Rosselló, Lisa Lindström, Greta Eklund, Matthieu Corvaisier and Maria Alvarado Kristensson
Int. J. Mol. Sci. 2018, 19(10), 3245; https://doi.org/10.3390/ijms19103245 - 19 Oct 2018
Cited by 16 | Viewed by 5049
Abstract
In cytoplasm, protein γ-tubulin joins with various γ-tubulin complex proteins (GCPs) to form a heterotetramer γ-tubulin small complex (γ-TuSC) that can grow into a ring-shaped structure called the γ-tubulin ring complex (γ-TuRC). Both γ-TuSC and γ-TuRC are required for microtubule nucleation. Recent knowledge [...] Read more.
In cytoplasm, protein γ-tubulin joins with various γ-tubulin complex proteins (GCPs) to form a heterotetramer γ-tubulin small complex (γ-TuSC) that can grow into a ring-shaped structure called the γ-tubulin ring complex (γ-TuRC). Both γ-TuSC and γ-TuRC are required for microtubule nucleation. Recent knowledge on γ-tubulin with regard to its cellular functions beyond participation in its creation of microtubules suggests that this protein forms a cellular meshwork. The present review summarizes the recognized functions of γ-tubulin and aims to unite the current views on this protein. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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Other

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1 pages, 178 KiB  
Correction
Correction: Cuenca-Zamora, Ernesto José., et al. Tubulin in Platelets: When the Shape Matter. Int. J. Mol. Sci. 2019, 20, 3484
by Ernesto José Cuenca-Zamora, Francisca Ferrer-Marín, José Rivera and Raúl Teruel-Montoya
Int. J. Mol. Sci. 2020, 21(10), 3577; https://doi.org/10.3390/ijms21103577 - 19 May 2020
Cited by 2 | Viewed by 1422
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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