Article
Multidisciplinary Sciences
Maxim Igaev, Helmut Grubmuller
Summary: This study uses atomistic simulations to investigate the bending and relaxation behavior of microtubule tips, revealing the dominance of viscoelastic dynamics. The posthydrolysis microtubule tip is unable to elongate due to higher activation energy barriers for straight lattice formation. This research provides an information-driven mechanism for the elastic energy conversion and release by microtubule tips.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biophysics
Shine Ayyappan, Pooja S. Dharan, Arya Krishnan, Renjith R. Marira, Mahil Lambert, Tapas K. Manna, Vinesh Vijayan
Summary: The SxIP peptide promotes the dissociation of EB1 dimer and induces folding of the EB1 C-terminal domain upon binding; Molecular dynamics simulations confirm the relative structural stability of EB1 in the SxIP bound state; The binding of SxIP peptide decreases the dynamics and conformational flexibility of the EB1 N-terminal domain involved in microtubule interaction.
BIOPHYSICAL JOURNAL
(2021)
Article
Multidisciplinary Sciences
Julie Miesch, Robert T. Wimbish, Marie- Claire Velluz, Charlotte Aumeier
Summary: This study reveals that microtubule end-binding proteins CLIP-170 and EB3 undergo phase separation to form dense liquid networks, which can concentrate tubulin and regulate microtubule growth dynamics.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Veronica J. Farmer, Marija Zanic
Summary: Almost 40 years since the discovery of microtubule dynamic instability, the molecular mechanisms underlying microtubule dynamics remain an area of intense research interest. Recent studies challenge the standard model of microtubule dynamics, proposing a new perspective where dynamic transitions between different structural conformations of the growing microtubule end ultimately drive microtubule catastrophe.
Article
Genetics & Heredity
Ines Hahn, Andre Voelzmann, Jill Parkin, Judith B. Fulle, Paula G. Slater, Laura Anne Lowery, Natalia Sanchez-Soriano, Andreas Prokop
Summary: The study reveals that the proteins Eb1, XMAP215/Msps, and Tau cooperate to regulate microtubule polymerisation and bundle organization, offering new conceptual explanations for axon pathologies.
Article
Cell Biology
Paul R. Elliott, Derek Leske, Jane Wagstaff, Lisa Schlicher, Georgina Berridge, Sarah Maslen, Frederik Timmermann, Biao Ma, Roman Fischer, Stefan M. Freund, David Komander, Mads Gyrd-Hansen
Summary: CYLD, together with SPATA2 and LUBAC, acts as a ubiquitin-editing complex to balance different types of ubiquitin chains at receptor signaling complexes, promoting signal transduction through factors such as activity and phosphorylation.
Article
Multidisciplinary Sciences
Yueh-Fu O. Wu, Annamarie T. Bryant, Nora T. Nelson, Alexander G. Madey, Gail F. Fernandes, Holly V. Goodson
Summary: The study examines the role of +TIPs in microtubule regulation and suggests that the +TIP network may form biomolecular condensates. This is supported by the observation of phase-separated liquid condensates induced by CLIP-170 in cells, which contain +TIP proteins and exhibit characteristics indicative of biomolecular condensates.
Article
Multidisciplinary Sciences
Xiangyu Fan, Richard J. McKenney
Summary: This study reveals the crucial role of a specialized kinesin tail domain in directing motor transport along specific microtubule tracks. The tail domain affects the initial motor-microtubule interaction and the processive motility, and its effect is enhanced when the motor domain is in the ADP state.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Ting-Yu Chen, Tzu-Chien Lin, Pao-Lin Kuo, Zi-Rong Chen, Hui-ling Cheng, Yu-Ying Chao, Jhih-Siang Syu, Fu- Lu, Chia-Yih Wang
Summary: SEPT7 plays a crucial role in maintaining proper cell proliferation and microtubule array formation by interacting with p150(glued) at the centrosome. Depletion of SEPT7 leads to mitotic defects, disorganized microtubule nucleation, and reduced cell migration, while overexpression of p150(glued) rescues the defective phenotypes. These findings highlight the importance of SEPT7 in regulating cell division and organization.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Article
Cell Biology
Veronica Farmer, Goker Arpa, Sarah L. Hall, Marija Zanic
Summary: The GTP-tubulin cap is believed to protect microtubules against catastrophe, but microtubules polymerized with XMAP215 display increased catastrophe frequency despite larger GTP-cap size. Structural perturbations induced by XMAP215 may override the protective effects of the GTP-cap.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Meghann C. Ma, Gaojin Li, Xinye Chen, Lynden A. Archer, Jiandi Wan
Summary: The study showed that introducing forced convection during electrodeposition process can effectively reduce metal dendrite growth and delay the onset of electroconvective instabilities, highlighting the potential of forced convection in managing the consequences of instability in electrokinetics-based processes.
Article
Mechanics
Antonio Posa, Riccardo Broglia, Elias Balaras
Summary: Large-eddy simulation is used to reproduce the instability of tip vortices shed from axial-flow turbine blades, showing that interactions between the vortices accelerate destabilization and lead to turbulence production. This process promotes momentum recovery and wake contraction by triggering intense mixing between the outer free stream and the inner wake flow downstream.
JOURNAL OF FLUID MECHANICS
(2021)
Article
Multidisciplinary Sciences
Benjamin J. LaFrance, Johanna Roostalu, Gil Henkin, Basil J. Greber, Rui Zhang, Davide Normanno, Chloe O. McCollum, Thomas Surrey, Eva Nogales
Summary: By studying GTP hydrolysis-deficient MTs, we found that their lattice structure is remarkably plastic, distinct from wild-type GDP-MTs. End-binding proteins of the EB family have the ability to affect the structure of mutant GTP lattices and promote the transition of the GTP cap. The seam plays an important role in MT stability.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Physics, Fluids & Plasmas
S. Ito, K. Y. Watanabe, Y. Takemura, S. Sakakibara, S. Masamune
Summary: This study experimentally investigates the impact of external resonant magnetic perturbation (RMP) on the resistive interchange MHD instability commonly observed in the Large Helical Device. By applying an m/n = 1/1 external RMP to discharges with m/n = 1/1 interchange instability, it is found that the electron density fluctuation and magnetic field fluctuation are both clearly reduced without a reduction in the pressure gradient. Furthermore, under certain conditions, the achieved beta value and beta gradient at the resonant surface show slight improvement. The study also explores the response of the interchange instability to the external RMP under different operational conditions, finding that the amplitude of the external RMP required for complete suppression of the instability has a higher correlation with the volume-averaged beta value compared to other plasma parameters.
Article
Biochemistry & Molecular Biology
Dae-Wook Yang, Kwang-Wook Choi
Summary: The study reveals the crucial roles of Patronin and Klp10A in regulating cell survival and organ size in Drosophila. Patronin inhibits the severing function of Spas at microtubule minus ends, and interacts with Diap1 and Hippo pathway genes. Overexpression of Klp10A reduces organ size, which can be partially suppressed by regulation of Diap1 or Hippo pathway genes.
CELL DEATH AND DIFFERENTIATION
(2021)
Editorial Material
Biochemistry & Molecular Biology
Kyung S. Lee, Michel O. Steinmetz
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ashwani Sharma, Natacha Olieric, Michel O. Steinmetz
Summary: Centrioles are microtubule-based structures crucial for cell division and ciliogenesis. Proteins controlling centriole length can be categorized into CEAs and CEIs, with antagonistic activities on centriolar microtubules. The review discusses the structure-function relationship and open questions in the field, suggesting potential directions for future studies.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Tobias Muehlethaler, Dario Gioia, Andrea E. Prota, May E. Sharpe, Andrea Cavalli, Michel O. Steinmetz
Summary: Using a combined computational and crystallographic approach, researchers identified 27 distinct binding sites in tubulin, including 11 previously unknown sites. They also observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. These results provide a structural basis for developing novel small molecules as tubulin modulators and lay down a framework that may aid in discovering new pockets in other pharmaceutically important targets.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Anil Kumar, Sandro M. Meier, Ana-Maria Farcas, Cristina Manatschal, Yves Barral, Michel O. Steinmetz
Summary: The study reveals the crystal structure of Kar9's folded domain, showing spectrin repeats similar to other +TIPs. Mutations disrupting spectrin-repeat-mediated dimerization of Kar9 affects its distribution to microtubule tips and spindle positioning. Phosphomimetic substitution at Cdk1 sites inhibits Kar9 dimerization, displaces Kar9 from microtubules, and affects its interaction with the myosin motor Myo2.
Article
Medicine, Research & Experimental
Natacha Gaillard, Ashwani Sharma, Izra Abbaali, Tianyang Liu, Fiona Shilliday, Alexander D. Cook, Valentin Ehrhard, Mamata Bangera, Anthony J. Roberts, Carolyn A. Moores, Naomi Morrissette, Michel O. Steinmetz
Summary: This study presents the rational design of a parasite-specific tubulin inhibitor, which inhibits parasite growth without affecting human cells, based on the atomic structures of protozoan tubulin and microtubules. This work provides a framework to exploit structural differences between human and protozoan tubulins, enabling the development of novel parasite inhibitors.
EMBO MOLECULAR MEDICINE
(2021)
Article
Chemistry, Multidisciplinary
Tobias Muhlethaler, Lampros Milanos, Jose Antonio Ortega, Thorsten B. Blum, Dario Gioia, Bibhas Roy, Andrea E. Prota, Andrea Cavalli, Michel O. Steinmetz
Summary: This study developed an antitubulin small molecule, Todalam, through two rounds of chemical synthesis based on a crystallographic fragment screen. Todalam binds to a novel tubulin site, disrupts microtubule networks, induces cell death, and synergizes with vinblastine. It destabilizes microtubules by inhibiting the conformational switch in alpha-tubulin and sequestering tubulin dimers. This work demonstrates the importance of using tubulin-binding fragments for innovative antitubulin drug and chemical probe discovery campaigns.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Li Gao, Joyce C. M. Meiring, Adam Varady, Iris E. Ruider, Constanze Heise, Maximilian Wranik, Cecilia D. Velasco, Jennifer A. Taylor, Beatrice Terni, Tobias Weinert, Jorg Standfuss, Clemens C. Cabernard, Artur Llobet, Michel O. Steinmetz, Andreas R. Bausch, Martin Distel, Julia Thorn-Seshold, Anna Akhmanova, Oliver Thorn-Seshold
Summary: Photoswitchable reagents have great potential in high-precision studies in cell biology. However, their in vivo application remains largely unrealized. In this study, we optimized the potency and solubility of photoswitchable reagents and successfully achieved high-precision research in microtubule dynamics, network architecture, and microtubule-dependent processes. The design of these reagents can also inspire the development of optical reagents for other cytosolic protein targets, advancing the field of in vivo photopharmacology.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
Noelia Montel de la Roche, Tobias Muehlethaler, Rita Maria Concetta Di Martino, Jose Antonio Ortega, Dario Gioia, Bibhas Roy, Andrea E. Prota, Michel O. Steinmetz, Andrea Cavalli
Summary: This study identified tubulin-binding fragments through computational and crystallographic screening, and used a rational design strategy to develop a new series of 2-aminobenzimidazole derivatives that destabilize microtubules. The synthesized compound showed submicromolar activity in inhibiting cell viability and demonstrated a similar mechanism of action as classical colchicine-binding site ligands.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Marilia Barreca, Virginia Span, Roberta Rocca, Roberta Bivacqua, Anne -Catherine Abel, Annalisa Maruca, Alessandra Montalbano, Maria Valeria Raimondi, Chiara Tarantelli, Eugenio Gaudio, Luciano Cascione, Andrea Rinaldi, Ruoli Bai, Michel O. Steinmetz, Andrea E. Prota, Stefano Alcaro, Ernest Hamel, Francesco Bertoni, Paola Barraja
Summary: Lymphomas are common cancers and require more effective therapeutic approaches. This study identified a series of oxazolo isoindoles as potential candidates for the treatment of refractory lymphomas due to their ability to bind to tubulin.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Sandro M. Meier, Ana-Maria Farcas, Anil Kumar, Mahdiye Ijavi, Robert T. Bill, Joerg Stelling, Eric R. Dufresne, Michel O. Steinmetz, Yves Barral
Summary: This study investigates the interactions and functions of the Kar9 network in yeast cells, finding that it forms a liquid condensate at selected microtubule ends, serving as a mechanical coupling between microtubules and actin cables.
NATURE CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Juan Estevez-Gallego, Beatriz Alvarez-Bernard, Benet Pera, Christoph Wullschleger, Olivier Raes, Dirk Menche, Juan Carlos Martinez, Daniel Lucena-Agell, Andrea E. Prota, Francesca Bonato, Katja Bargsten, Jelle Cornelus, Juan Francisco Gimenez-Abian, Peter Northcote, Michel O. Steinmetz, Shinji Kamimura, Karl-Heinz Altmann, Ian Paterson, Federico Gago, Johan Van der Eycken, J. Fernando Diaz, Maria Angela Oliva
Summary: Taxanes are microtubule-stabilizing agents used in cancer treatment, but they have side effects on the peripheral nervous system. This study investigates the stabilization mechanism of laulimalide and peloruside, which bind to a different site and can modulate the diameter of microtubules. Some compounds with low cytotoxicity are found to induce stabilization without compromising the native structure of microtubules, suggesting potential applications beyond cancer treatment.
Article
Biology
Charlotte Guyomar, Clement Bousquet, Siou Ku, John M. Heumann, Gabriel Guilloux, Natacha Gaillard, Claire Heichette, Laurence Duchesne, Michel O. Steinmetz, Romain Gibeaux, Denis Chretien, Julie P. Welburn
Summary: Microtubules, structures with a diameter of about 25 nm, play critical roles in cellular functions such as motility, compartmentalization, and division. This study reveals that microtubules consist of variable numbers of protofilaments and tubulin subunit helical-starts, as well as variable numbers of seams. Interestingly, the number and location of seams vary along individual microtubules, leading to the formation of holes within their lattices. These findings demonstrate that the organization of microtubules is an intrinsic property of tubulin and requires unique lateral interactions without longitudinal ones.
Article
Biochemistry & Molecular Biology
Li Gao, Joyce C. M. Meiring, Yvonne Kraus, Maximilian Wranik, Tobias Weinert, Stefanie D. Pritzl, Rebekkah Bingham, Evangelia Ntouliou, Klara Jansen, Natacha Olieric, Jorg Standfuss, Lukas C. Kapitein, Theobald Lohmuller, Julia Ahlfeld, Anna Akhmanova, Michel O. Steinmetz, Oliver Thorn-Seshold
Summary: Researchers have designed a photoswitchable SBT scaffold to create metabolically stable and fully GFP/YFP-orthogonal SBTub photopharmaceuticals for precise control of microtubule dynamics and organization. These photopharmaceuticals have great potential applications in cell biology and are favorable for intracellular biological control in in vivo settings. The robustness and imaging orthogonality of the SBT scaffold may inspire further derivatizations for photocontrol of a range of other biological targets.
CELL CHEMICAL BIOLOGY
(2021)
Meeting Abstract
Biophysics
Joseph Atherton, Jessica J. Hummel, Natacha Olieric, Michel O. Steinmetz, Anna Akhmanova, Casper Hoogenraad, Carolyn A. Moores
BIOPHYSICAL JOURNAL
(2021)
Article
Chemistry, Physical
Mahdiye Ijavi, Robert W. Style, Leonidas Emmanouilidis, Anil Kumar, Sandro M. Meier, Alexandre L. Torzynski, Frederic H. T. Allain, Yves Barral, Michel O. Steinmetz, Eric R. Dufresne
Summary: This study demonstrates a classic method that can be effectively scaled down to measure the surface tension of liquid droplets based on droplet shape and density differences. The connection between droplet shape and surface tension relies on the density difference, which can be determined with the measurement of droplet sedimentation velocity in the same setup.