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Control of Tubulin Structure and Function by Accessory Proteins and Drugs

English title Control of Tubulin Structure and Function by Accessory Proteins and Drugs
Applicant Steinmetz Michel
Number 166608
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Biochemistry
Start/End 01.04.2016 - 30.04.2020
Approved amount 976'746.00
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Keywords (10)

Biochemistry; X-ray crystallography; Structure-function relationship; Protein-protein interaction; Microtubule associated proteins; Structural Biology; Microtubule targeting agents; Centriolar proteins; Protein-ligand interaction; Microtubules

Lay Summary (German)

Lead
Strukturelle und funktionelle Charakterisierung von Tubulin und assoziierten Liganden
Lay summary

Mikrotubuli sind dynamische, faserartige Proteinstrukturen des Zellskeletts, welche unter anderem bei der Zellteilung, Zellbewegung und intrazellulärem Transport eine zentrale Rolle spielen. Sie sind zudem für den Aufbau von Zentriolen, Zilien und Flagellen zuständig. Weil Mikrotubuli und deren assoziierten Proteine wichtige biologische Funktionen in allen menschlichen Zellen ausüben, stellen sie attraktive Ansatzpunkte dar, um Krebs, neurologische Störungen und Ziliopathien behandeln zu können. Um neuartige Strategien zur Behandlung dieser stetig anwachsenden Zahl von Krankheiten zu entwickeln, ist ein detailliertes strukturelles Verständnis der Mikrotubuli und wie diese mit assoziierten Proteinen und Liganden interagieren von Nöten. Unsere Gruppe hat in den letzten Jahren Methoden entwickelt, welche erlauben, den Grundbaustein der Mikrotubuli, das Protein Tubulin, bei hoher Auflösung mittels Röntgenkristallographie zu untersuchen. Unsere Arbeiten haben bereits zum Verständnis des Wirkmechanismus einzelner Liganden, welche das Tubulin binden, beigetragen. In diesem Gesuch planen wir nun unsere Methodik weiter zu entwickeln. Zwei wichtige Hauptziele sollen dabei erarbeitet werden:

1. Erstellen einer detaillierten Grundlage um zu verstehen, wie potentielle Krebsmedikamente die Struktur und die Dynamik des Tubulins beeinflussen.

2. Analyse der Strukturen und biologischen Funktionen von Schlüsselproteinen, welche die Dynamik der Mikrotubuli im Zytoplasma, in den Zentriolen und in Zilien steuern.

Die vorgeschlagenen Studien werden zum tieferen Verständnis von Schlüsselfaktoren, welche das Verhalten der Mikrotubuli beeinflussen, beitragen. Sie werden deshalb eine wichtige Grundlage zur Entwicklung neuer Strategien gegen verschiedene, menschliche Krankheiten darstellen.

Direct link to Lay Summary Last update: 16.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Structural model for differential cap maturation at growing microtubule ends
Estévez-Gallego Juan, Josa-Prado Fernando, Ku Siou, Buey Ruben M, Balaguer Francisco A, Prota Andrea E, Lucena-Agell Daniel, Kamma-Lorger Christina, Yagi Toshiki, Iwamoto Hiroyuki, Duchesne Laurence, Barasoain Isabel, Steinmetz Michel O, Chrétien Denis, Kamimura Shinji, Díaz J Fernando, Oliva Maria A (2020), Structural model for differential cap maturation at growing microtubule ends, in eLife, 9.
Taxanes convert regions of perturbed microtubule growth into rescue sites
Rai Ankit, Liu Tianyang, Glauser Simon, Katrukha Eugene A., Estévez-Gallego Juan, Rodríguez-García Ruddi, Fang Wei-Shuo, Díaz J. Fernando, Steinmetz Michel O., Altmann Karl-Heinz, Kapitein Lukas C., Moores Carolyn A., Akhmanova Anna (2020), Taxanes convert regions of perturbed microtubule growth into rescue sites, in Nature Materials, 19(3), 355-365.
Mechanisms of Motor-Independent Membrane Remodeling Driven by Dynamic Microtubules
Rodríguez-García Ruddi, Volkov Vladimir A., Chen Chiung-Yi, Katrukha Eugene A., Olieric Natacha, Aher Amol, Grigoriev Ilya, López Magdalena Preciado, Steinmetz Michel O., Kapitein Lukas C., Koenderink Gijsje, Dogterom Marileen, Akhmanova Anna (2020), Mechanisms of Motor-Independent Membrane Remodeling Driven by Dynamic Microtubules, in Current Biology, 30(6), 972-987.e12.
Structural determinants of microtubule minus end preference in CAMSAP CKK domains
Atherton Joseph, Luo Yanzhang, Xiang Shengqi, Yang Chao, Rai Ankit, Jiang Kai, Stangier Marcel, Vemu Annapurna, Cook Alexander D., Wang Su, Roll-Mecak Antonina, Steinmetz Michel O., Akhmanova Anna, Baldus Marc, Moores Carolyn A. (2019), Structural determinants of microtubule minus end preference in CAMSAP CKK domains, in Nature Communications, 10(1), 5236-5236.
Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia
Cury Nathália Moreno, Mühlethaler Tobias, Laranjeira Angelo Brunelli Albertoni, Canevarolo Rafael Renatino, Zenatti Priscila Pini, Lucena-Agell Daniel, Barasoain Isabel, Song Chunhua, Sun Dongxiao, Dovat Sinisa, Yunes Rosendo Augusto, Prota Andrea Enrico, Steinmetz Michel Olivier, Díaz José Fernando, Yunes José Andrés (2019), Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia, in iScience, 21, 95-109.
Remote control of microtubule plus-end dynamics and function from the minus-end
Chen Xiuzhen, Widmer Lukas A, Stangier Marcel M, Steinmetz Michel O, Stelling Jörg, Barral Yves (2019), Remote control of microtubule plus-end dynamics and function from the minus-end, in eLife, 8, pii: e4862.
Crystal Structure of a Heterotetrameric Katanin p60:p80 Complex
Faltova Lenka, Jiang Kai, Frey Daniel, Wu Yufan, Capitani Guido, Prota Andrea E., Akhmanova Anna, Steinmetz Michel O., Kammerer Richard A. (2019), Crystal Structure of a Heterotetrameric Katanin p60:p80 Complex, in Structure, 27(9), 1375-1383.e3.
GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses
Kashyap Abhishek S., Fernandez-Rodriguez Laura, Zhao Yun, Monaco Gianni, Trefny Marcel P., Yoshida Naohiro, Martin Kea, Sharma Ashwani, Olieric Natacha, Shah Pankaj, Stanczak Michal, Kirchhammer Nicole, Park Sung-Moo, Wieckowski Sebastien, Laubli Heinz, Zagani Rachid, Kasenda Benjamin, Steinmetz Michel O., Reinecker Hans-Christian, Zippelius Alfred (2019), GEF-H1 Signaling upon Microtubule Destabilization Is Required for Dendritic Cell Activation and Specific Anti-tumor Responses, in Cell Reports, 28(13), 3367-3380.e8.
Structural basis of tubulin detyrosination by the vasohibin–SVBP enzyme complex
Wang Na, Bosc Christophe, Ryul Choi Sung, Boulan Benoit, Peris Leticia, Olieric Natacha, Bao Hongyu, Krichen Fatma, Chen Liu, Andrieux Annie, Olieric Vincent, Moutin Marie-Jo, Steinmetz Michel O., Huang Hongda (2019), Structural basis of tubulin detyrosination by the vasohibin–SVBP enzyme complex, in Nature Structural & Molecular Biology, 26(7), 571-582.
VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells
Patterson Jesse C., Joughin Brian A., Prota Andrea E., Mühlethaler Tobias, Jonas Oliver H., Whitman Matthew A., Varmeh Shohreh, Chen Sen, Balk Steven P., Steinmetz Michel O., Lauffenburger Douglas A., Yaffe Michael B. (2019), VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells, in Cell Systems, 9(1), 74-92.e8.
Microtubule minus-end regulation at a glance
Akhmanova Anna, Steinmetz Michel O. (2019), Microtubule minus-end regulation at a glance, in Journal of Cell Science, 132(11), jcs227850-jcs227850.
MAP7 family proteins regulate kinesin-1 recruitment and activation
Hooikaas Peter Jan, Martin Maud, Mühlethaler Tobias, Kuijntjes Gert-Jan, Peeters Cathelijn A.E., Katrukha Eugene A., Ferrari Luca, Stucchi Riccardo, Verhagen Daan G.F., van Riel Wilhelmina E., Grigoriev Ilya, Altelaar A.F. Maarten, Hoogenraad Casper C., Rüdiger Stefan G.D., Steinmetz Michel O., Kapitein Lukas C., Akhmanova Anna (2019), MAP7 family proteins regulate kinesin-1 recruitment and activation, in Journal of Cell Biology, 218(4), 1298-1318.
Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands
Balaguer Francisco, Mühlethaler Tobias, Estévez-Gallego Juan, Calvo Enrique, Giménez-Abián Juan, Risinger April, Sorensen Erik, Vanderwal Christopher, Altmann Karl-Heinz, Mooberry Susan, Steinmetz Michel, Oliva María, Prota Andrea, Díaz J. (2019), Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands, in International Journal of Molecular Sciences, 20(6), 1392-1392.
Conformational Properties of the Chemotherapeutic Drug Analogue Epothilone A: How to Model a Flexible Protein Ligand Using Scarcely Available Experimental Data
Dolenc Jožica, van Gunsteren Wilfred F., Prota Andrea E., Steinmetz Michel O., Missimer John H. (2019), Conformational Properties of the Chemotherapeutic Drug Analogue Epothilone A: How to Model a Flexible Protein Ligand Using Scarcely Available Experimental Data, in Journal of Chemical Information and Modeling, 59(5), 2218-2230.
Tetrahydroisoquinoline Sulfamates as Potent Microtubule Disruptors: Synthesis, Antiproliferative and Antitubulin Activity of Dichlorobenzyl-Based Derivatives, and a Tubulin Cocrystal Structure
Dohle Wolfgang, Prota Andrea E., Menchon Grégory, Hamel Ernest, Steinmetz Michel O., Potter Barry V. L. (2019), Tetrahydroisoquinoline Sulfamates as Potent Microtubule Disruptors: Synthesis, Antiproliferative and Antitubulin Activity of Dichlorobenzyl-Based Derivatives, and a Tubulin Cocrystal Structure, in ACS Omega, 4(1), 755-764.
Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents
Brindisi Margherita, Ulivieri Cristina, Alfano Gloria, Gemma Sandra, de Asís Balaguer Francisco, Khan Tuhina, Grillo Alessandro, Chemi Giulia, Menchon Grégory, Prota Andrea E., Olieric Natacha, Lucena-Agell Daniel, Barasoain Isabel, Diaz J. Fernando, Nebbioso Angela, Conte Mariarosaria, Lopresti Ludovica, Magnano Stefania, Amet Rebecca, Kinsella Paula, Zisterer Daniela M., Ibrahim Ola, O'Sullivan Jeff, Morbidelli Lucia, et al. (2019), Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents, in European Journal of Medicinal Chemistry, 162, 290-320.
A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin
Menchon Grégory, Prota Andrea E., Lucena-Agell Daniel, Bucher Pascal, Jansen Rolf, Irschik Herbert, Müller Rolf, Paterson Ian, Díaz J. Fernando, Altmann Karl-Heinz, Steinmetz Michel O. (2018), A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin, in Nature Communications, 9(1), 2106-2106.
Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
Smedley Christopher J., Stanley Paul A., Qazzaz Mohannad E., Prota Andrea E., Olieric Natacha, Collins Hilary, Eastman Harry, Barrow Andrew S., Lim Kuan-Hon, Kam Toh-Seok, Smith Brian J., Duivenvoorden Hendrika M., Parker Belinda S., Bradshaw Tracey D., Steinmetz Michel O., Moses John E. (2018), Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site, in Scientific Reports, 8(1), 10617-10617.
High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design
Bueno Oskía, Estévez Gallego Juan, Martins Solange, Prota Andrea E., Gago Federico, Gómez-SanJuan Asier, Camarasa María-José, Barasoain Isabel, Steinmetz Michel O., Díaz J. Fernando, Pérez-Pérez María-Jesús, Liekens Sandra, Priego Eva-María (2018), High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design, in Scientific Reports, 8(1), 4242-4242.
Combinatorial use of disulfide bridges and native sulfur-SAD phasing for rapid structure determination of coiled-coils
Kraatz Sebastian H.W., Bianchi Sarah, Steinmetz Michel O. (2018), Combinatorial use of disulfide bridges and native sulfur-SAD phasing for rapid structure determination of coiled-coils, in Bioscience Reports, 38(5), pii: BSR2.
Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton
Steinmetz Michel O., Prota Andrea E. (2018), Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton, in Trends in Cell Biology, 28(10), 776-792.
Cep120 promotes microtubule formation through a unique tubulin binding C2 domain
Sharma Ashwani, Gerard Samuel F., Olieric Natacha, Steinmetz Michel O. (2018), Cep120 promotes microtubule formation through a unique tubulin binding C2 domain, in Journal of Structural Biology, 203(1), 62-70.
CLASP Suppresses Microtubule Catastrophes through a Single TOG Domain
Aher Amol, Kok Maurits, Sharma Ashwani, Rai Ankit, Olieric Natacha, Rodriguez-Garcia Ruddi, Katrukha Eugene A., Weinert Tobias, Olieric Vincent, Kapitein Lukas C., Steinmetz Michel O., Dogterom Marileen, Akhmanova Anna (2018), CLASP Suppresses Microtubule Catastrophes through a Single TOG Domain, in Developmental Cell, 46(1), 40-58.e8.
Structure-Function Relationship of the Bik1-Bim1 Complex
Stangier Marcel M., Kumar Anil, Chen Xiuzhen, Farcas Ana-Maria, Barral Yves, Steinmetz Michel O. (2018), Structure-Function Relationship of the Bik1-Bim1 Complex, in Structure, 26(4), 607-618.e4.
Interaction between the Caenorhabditis elegans centriolar protein SAS-5 and microtubules facilitates organelle assembly
Bianchi Sarah, Rogala Kacper B., Dynes Nicola J., Hilbert Manuel, Leidel Sebastian A., Steinmetz Michel O., Gönczy Pierre, Vakonakis Ioannis (2018), Interaction between the Caenorhabditis elegans centriolar protein SAS-5 and microtubules facilitates organelle assembly, in Molecular Biology of the Cell, 29(6), 722-735.
Structural Basis of Formation of the Microtubule Minus-End-Regulating CAMSAP-Katanin Complex
Jiang Kai, Faltova Lenka, Hua Shasha, Capitani Guido, Prota Andrea E., Landgraf Christiane, Volkmer Rudolf, Kammerer Richard A., Steinmetz Michel O., Akhmanova Anna (2018), Structural Basis of Formation of the Microtubule Minus-End-Regulating CAMSAP-Katanin Complex, in Structure, 26(3), 375-382.e4.
Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure
Dohle Wolfgang, Jourdan Fabrice L., Menchon Grégory, Prota Andrea E., Foster Paul A., Mannion Pascoe, Hamel Ernest, Thomas Mark P., Kasprzyk Philip G., Ferrandis Eric, Steinmetz Michel O., Leese Mathew P., Potter Barry V. L. (2018), Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure, in Journal of Medicinal Chemistry, 61(3), 1031-1044.
Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons
Weinert Tobias, Olieric Natacha, Cheng Robert, Brünle Steffen, James Daniel, Ozerov Dmitry, Gashi Dardan, Vera Laura, Marsh May, Jaeger Kathrin, Dworkowski Florian, Panepucci Ezequiel, Basu Shibom, Skopintsev Petr, Doré Andrew S., Geng Tian, Cooke Robert M., Liang Mengning, Prota Andrea E., Panneels Valerie, Nogly Przemyslaw, Ermler Ulrich, Schertler Gebhard, Hennig Michael, et al. (2017), Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons, in Nature Communications, 8(1), 542-542.
Structural basis of katanin p60:p80 complex formation
Rezabkova Lenka, Jiang Kai, Capitani Guido, Prota Andrea E., Akhmanova Anna, Steinmetz Michel O., Kammerer Richard A. (2017), Structural basis of katanin p60:p80 complex formation, in Scientific Reports, 7(1), 14893-14893.
A structural model for microtubule minus-end recognition and protection by CAMSAP proteins
Atherton Joseph, Jiang Kai, Stangier Marcel M, Luo Yanzhang, Hua Shasha, Houben Klaartje, van Hooff Jolien J E, Joseph Agnel-Praveen, Scarabelli Guido, Grant Barry J, Roberts Anthony J, Topf Maya, Steinmetz Michel O, Baldus Marc, Moores Carolyn A, Akhmanova Anna (2017), A structural model for microtubule minus-end recognition and protection by CAMSAP proteins, in Nature Structural & Molecular Biology, 24(11), 931-943.
Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent
Jost Marco, Chen Yuwen, Gilbert Luke A., Horlbeck Max A., Krenning Lenno, Menchon Grégory, Rai Ankit, Cho Min Y., Stern Jacob J., Prota Andrea E., Kampmann Martin, Akhmanova Anna, Steinmetz Michel O., Tanenbaum Marvin E., Weissman Jonathan S. (2017), Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent, in Molecular Cell, 68(1), 210-223.e6.
Identification of Chlamydomonas Central Core Centriolar Proteins Reveals a Role for Human WDR90 in Ciliogenesis
Hamel Virginie, Steib Emmanuelle, Hamelin Romain, Armand Florence, Borgers Susanne, Flückiger Isabelle, Busso Coralie, Olieric Natacha, Sorzano Carlos Oscar S., Steinmetz Michel O., Guichard Paul, Gönczy Pierre (2017), Identification of Chlamydomonas Central Core Centriolar Proteins Reveals a Role for Human WDR90 in Ciliogenesis, in Current Biology, 27(16), 2486-2498.e6.
Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin
Sharma Ashwani, Sáez-Calvo Gonzalo, Olieric Natacha, de Asís Balaguer Francisco, Barasoain Isabel, Lamberth Clemens, Díaz J., Steinmetz Michel (2017), Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin, in International Journal of Molecular Sciences, 18(7), 1336-1336.
Short Linear Sequence Motif LxxPTPh Targets Diverse Proteins to Growing Microtubule Ends
Kumar Anil, Manatschal Cristina, Rai Ankit, Grigoriev Ilya, Degen Miriam Steiner, Jaussi Rolf, Kretzschmar Ines, Prota Andrea E., Volkmer Rudolf, Kammerer Richard A., Akhmanova Anna, Steinmetz Michel O. (2017), Short Linear Sequence Motif LxxPTPh Targets Diverse Proteins to Growing Microtubule Ends, in Structure, 25(6), 924-932.e4.
Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
Sáez-Calvo Gonzalo, Sharma Ashwani, Balaguer Francisco de Asís, Barasoain Isabel, Rodríguez-Salarichs Javier, Olieric Natacha, Muñoz-Hernández Hugo, Berbís Manuel Álvaro, Wendeborn Sebastian, Peñalva Miguel Angel, Matesanz Ruth, Canales Ángeles, Prota Andrea Enrico, Jímenez-Barbero Jesús, Andreu José Manuel, Lamberth Clemens, Steinmetz Michel Olivier, Díaz José Fernando (2017), Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin, in Cell Chemical Biology, 24(6), 737-750.e6.
Microtubule minus-end regulation at spindle poles by an ASPM–katanin complex
Jiang Kai, Rezabkova Lenka, Hua Shasha, Liu Qingyang, Capitani Guido, Altelaar A. F. Maarten, Heck Albert J. R., Kammerer Richard A., Steinmetz Michel O., Akhmanova Anna (2017), Microtubule minus-end regulation at spindle poles by an ASPM–katanin complex, in Nature Cell Biology, 19(5), 480-492.
Structural Basis of Microtubule Stabilization by Discodermolide
Prota Andrea E., Bargsten Katja, Redondo-Horcajo Mariano, Smith Amos B., Yang Chia-Ping H., McDaid Hayley M., Paterson Ian, Horwitz Susan B., Fernando Díaz José, Steinmetz Michel O. (2017), Structural Basis of Microtubule Stabilization by Discodermolide, in ChemBioChem, 18(10), 905-909.
Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention
Bohnacker Thomas, Prota Andrea E., Beaufils Florent, Burke John E., Melone Anna, Inglis Alison J., Rageot Denise, Sele Alexander M., Cmiljanovic Vladimir, Cmiljanovic Natasa, Bargsten Katja, Aher Amol, Akhmanova Anna, Díaz J. Fernando, Fabbro Doriano, Zvelebil Marketa, Williams Roger L., Steinmetz Michel O., Wymann Matthias P. (2017), Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention, in Nature Communications, 8(1), 14683-14683.
Kinesin-4 KIF21B is a potent microtubule pausing factor
van Riel Wilhelmina E, Rai Ankit, Bianchi Sarah, Katrukha Eugene A, Liu Qingyang, Heck Albert JR, Hoogenraad Casper C, Steinmetz Michel O, Kapitein Lukas C, Akhmanova Anna (2017), Kinesin-4 KIF21B is a potent microtubule pausing factor, in eLife, 6, e24746.
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091
Canela María-Dolores, Noppen Sam, Bueno Oskía, Prota Andrea E., Bargsten Katja, Sáez-Calvo Gonzalo, Jimeno María-Luisa, Benkheil Mohammed, Ribatti Domenico, Velázquez Sonsoles, Camarasa María-José, Fernando Díaz J., Steinmetz Michel O., Priego Eva-María, Pérez-Pérez María-Jesús, Liekens Sandra (2017), Antivascular and antitumor properties of the tubulin-binding chalcone TUB091, in Oncotarget, 8(9), 14325-14342.
Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells
Trigili Chiara, Barasoain Isabel, Sánchez-Murcia Pedro A., Bargsten Katja, Redondo-Horcajo Mariano, Nogales Aurora, Gardner Nicola M., Meyer Arndt, Naylor Guy J., Gómez-Rubio Elena, Gago Federico, Steinmetz Michel O., Paterson Ian, Prota Andrea E., Díaz J. Fernando (2016), Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells, in ACS Omega, 1(6), 1192-1204.
The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity
Wieczorek Michal, Tcherkezian Joseph, Bernier Cynthia, Prota Andrea E., Chaaban Sami, Rolland Yannève, Godbout Claude, Hancock Mark A., Arezzo Joseph C., Ocal Ozhan, Rocha Cecilia, Olieric Natacha, Hall Anita, Ding Hui, Bramoullé Alexandre, Annis Matthew G., Zogopoulos George, Harran Patrick G., Wilkie Thomas M., Brekken Rolf A., Siegel Peter M., Steinmetz Michel O., Shore Gordon C., Brouhard Gary J., et al. (2016), The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity, in Science Translational Medicine, 8(365), 365ra159-365ra159.
Molecular basis of Kar9-Bim1 complex function during mating and spindle positioning
Manatschal Cristina, Farcas Ana-Maria, Degen Miriam Steiner, Bayer Mathias, Kumar Anil, Landgraf Christiane, Volkmer Rudolf, Barral Yves, Steinmetz Michel O. (2016), Molecular basis of Kar9-Bim1 complex function during mating and spindle positioning, in Molecular Biology of the Cell, 27(23), 3729-3745.
Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations
Bianchi Sarah, van Riel Wilhelmina E., Kraatz Sebastian H. W., Olieric Natacha, Frey Daniel, Katrukha Eugene A., Jaussi Rolf, Missimer John, Grigoriev Ilya, Olieric Vincent, Benoit Roger M., Steinmetz Michel O., Akhmanova Anna, Kammerer Richard A. (2016), Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations, in Scientific Reports, 6(1), 30668-30668.
EB1 interacts with outwardly curved and straight regions of the microtubule lattice
Guesdon Audrey, Bazile Franck, Buey Rubén M., Mohan Renu, Monier Solange, García Ruddi Rodríguez, Angevin Morgane, Heichette Claire, Wieneke Ralph, Tampé Robert, Duchesne Laurence, Akhmanova Anna, Steinmetz Michel O., Chrétien Denis (2016), EB1 interacts with outwardly curved and straight regions of the microtubule lattice, in Nature Cell Biology, 18(10), 1102-1108.
Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network
Rezabkova Lenka, Kraatz Sebastian H. W., Akhmanova Anna, Steinmetz Michel O., Kammerer Richard A. (2016), Biophysical and Structural Characterization of the Centriolar Protein Cep104 Interaction Network, in Journal of Biological Chemistry, 291(35), 18496-18504.
Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics
Waight Andrew B., Bargsten Katja, Doronina Svetlana, Steinmetz Michel O., Sussman Django, Prota Andrea E. (2016), Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics, in PLOS ONE, 11(8), e0160890-e0160890.
The Human Centriolar Protein CEP135 Contains a Two-Stranded Coiled-Coil Domain Critical for Microtubule Binding
Kraatz Sebastian, Guichard Paul, Obbineni Jagan M., Olieric Natacha, Hatzopoulos Georgios N., Hilbert Manuel, Sen Indrani, Missimer John, Gönczy Pierre, Steinmetz Michel O. (2016), The Human Centriolar Protein CEP135 Contains a Two-Stranded Coiled-Coil Domain Critical for Microtubule Binding, in Structure, 24(8), 1358-1371.
Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies
Burger Dominique, Stihle Martine, Sharma Ashwani, Di Lello Paola, Benz Jörg, D'Arcy Brigitte, Debulpaep Maja, Fry David, Huber Walter, Kremer Thomas, Laeremans Toon, Matile Hugues, Ross Alfred, Rufer Arne C., Schoch Guillaume, Steinmetz Michel O., Steyaert Jan, Rudolph Markus G., Thoma Ralf, Ruf Armin (2016), Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies, in Journal of Biological Chemistry, 291(31), 16292-16306.
Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation
Prota Andrea E., Setter Jocelyn, Waight Andrew B., Bargsten Katja, Murga Juan, Diaz José Fernando, Steinmetz Michel O. (2016), Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation, in Journal of Molecular Biology, 428(15), 2981-2988.
Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes
Doodhi Harinath, Prota Andrea E., Rodríguez-García Ruddi, Xiao Hui, Custar Daniel W., Bargsten Katja, Katrukha Eugene A., Hilbert Manuel, Hua Shasha, Jiang Kai, Grigoriev Ilya, Yang Chia-Ping H., Cox David, Horwitz Susan Band, Kapitein Lukas C., Akhmanova Anna, Steinmetz Michel O. (2016), Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes, in Current Biology, 26(13), 1713-1721.
Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth
Sharma Ashwani, Aher Amol, Dynes Nicola J., Frey Daniel, Katrukha Eugene A., Jaussi Rolf, Grigoriev Ilya, Croisier Marie, Kammerer Richard A., Akhmanova Anna, Gönczy Pierre, Steinmetz Michel O. (2016), Centriolar CPAP/SAS-4 Imparts Slow Processive Microtubule Growth, in Developmental Cell, 37(4), 362-376.
SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture
Hilbert Manuel, Noga Akira, Frey Daniel, Hamel Virginie, Guichard Paul, Kraatz Sebastian H. W., Pfreundschuh Moritz, Hosner Sarah, Flückiger Isabelle, Jaussi Rolf, Wieser Mara M., Thieltges Katherine M., Deupi Xavier, Müller Daniel J., Kammerer Richard A., Gönczy Pierre, Hirono Masafumi, Steinmetz Michel O. (2016), SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture, in Nature Cell Biology, 18(4), 393-403.
Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity
Kevenaar Josta T., Bianchi Sarah, van Spronsen Myrrhe, Olieric Natacha, Lipka Joanna, Frias Cátia P., Mikhaylova Marina, Harterink Martin, Keijzer Nanda, Wulf Phebe S., Hilbert Manuel, Kapitein Lukas C., de Graaff Esther, Ahkmanova Anna, Steinmetz Michel O., Hoogenraad Casper C. (2016), Kinesin-Binding Protein Controls Microtubule Dynamics and Cargo Trafficking by Regulating Kinesin Motor Activity, in Current Biology, 26(7), 849-861.
Data-collection strategy for challenging native SAD phasing
Olieric Vincent, Weinert Tobias, Finke Aaron D., Anders Carolin, Li Dianfan, Olieric Natacha, Borca Camelia N., Steinmetz Michel O., Caffrey Martin, Jinek Martin, Wang Meitian (2016), Data-collection strategy for challenging native SAD phasing, in Acta Crystallographica Section D Structural Biology, 72(3), 421-429.

Collaboration

Group / person Country
Types of collaboration
Prof. Karl-Heinz Altman/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. John Moses/La Trobe University Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. John Vakonakis/University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Michael Yaffe/The Koch Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Andrea Cavalli/Italian Institute of Technology Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Anna Akhmanova/University of Utrecht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Martin Jinek/University of Zürich Switzerland (Europe)
- Publication
Dr. Denis Chretien/University of Rennes France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Pierre Gönczy/EPFL Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Alfred Zipelius/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Marie-Jo Moutin/University of Grenoble France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Fernando Diaz/Centro de Investigaciones Biologicas Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Barry Potter/University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ernesto Hamel/NIH United States of America (North America)
- Publication
Prof. Hongda Huang/Southern University of Science and Technology China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Pierre Gönczy/EPFL Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Yves Barral/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Daniel Müller/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Carolyn Moores/Birkbeck University London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Lukas Kapitein/Utrecht University Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Gary Brouhard/Mac Gill University Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Matthias Wymann/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Marvin Tanenbaum/Hubrecht Institute Netherlands (Europe)
- Publication
Prof. José Andrés Yunes/State University of Campinas Brazil (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Wilfred van Gunsteren/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Ian Paterson/University of Cambridge Great Britain and Northern Ireland (Europe)
- Publication
Prof. Marileen Dogterom/TU Delft Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jonathan Weissman/UC San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Sandra Liekens/KU Leuven Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Susan Horwitz/Einstein College of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jörg Stelling/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Marc Baldus/Utrecht University Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Rudolf Volkmer/Charite Berlin Germany (Europe)
- Publication
Prof. Casper Hoogenraad/University of Utrecht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Masafumi Hirono/Tokyo University Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
192566 Structure-activity relationship of microtubule regulators 01.05.2020 Project funding (Div. I-III)
138659 Protein interactions regulating the microtubule cytoskeleton 01.01.2012 Project funding (Div. I-III)
170802 Direct electron detector for cryo-EM single particle analysis, electron tomography and protein nanocrystallography 01.11.2017 R'EQUIP
177125 Tunable nanosecond laser for time-resolved serial crystallography at SLS and SwissFEL 01.01.2018 R'EQUIP

Abstract

Microtubules and their building block tubulin play important roles in several fundamental biological processes, including cell division, motility, cytoplasmic organization and intracellular trafficking. Besides being implicated in ‘classical’ cytoskeleton-based functions, microtubules are also key to build up the centrioles and axonemes of centrosomes, and cilia and flagella, respectively. Because of their outstanding importance, microtubules and their accessory proteins are attractive drug targets of high medical and industrial value for the treatment of a steadily increasing number of severe human diseases, including cancer, ciliopathies and neurological disorders. Understanding how regulatory proteins and drugs control the structure and function of tubulin and microtubules at the atomic level is essential for establishing a strong mechanistic basis for the development of strategies against these diseases, but represents a major challenge in contemporary microtubule cytoskeleton research. Addressing this fundamental problem necessitates the acquisition of high resolution structural information on tubulin and on its complexes with accessory factors, and linkage of this information with functional data. We are in an excellent position to provide the missing structural information: We have recently established unique tubulin structural biology tools that allow elucidating the mechanisms of action of accessory proteins and anticancer drugs to high resolution (1.8 Å) by X-ray crystallography. We will now capitalize on this important success and develop complementary structural, biophysical, biochemical and cell biology approaches to achieve the following goals:1. Establish a detailed and comprehensive mechanistic basis for understanding how anticancer drugs modulate the conformational dynamics of tubulin to control microtubule function.2. Elucidate the structure-function relationship of key proteins regulating microtubule dynamics in the cytoplasm, centrosomes and cilia. The proposed work will provide new insights into the mechanism of actions of key tubulin regulators at the atomic level and will thus establish a strong platform for the development of novel strategies against human diseases.
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