Dr. Andrea Prota

Curriculum Vitae

We use X-Ray crystallography in combination with biochemical and biophysical methods to provide the molecular mechanisms of protein interactions implicated in the regulation of the microtubule cytoskeleton. The elucidation and further exploration of these interactions at atomic resolution are pivotal to both basic and applied research in this field, and have important implications for the treatment of cancer and neurodegenerative diseases.

Our research activities are dedicated to the structural analysis of tubulin interactions with microtubule-targeting agents (MTAs). MTAs like taxol efficiently block cell entry into mitosis and are among the most potent chemotherapeutic drugs used for the treatment of different types of cancers. Despite the importance of MTAs for medical and basic research applications, their molecular mechanisms of action often remain elusive. Using X-ray crystallography and cryo EM we study the mechanisms of action of diverse MTAs by determining their structures in complex with tubulin and microtubules to high resolution.

Our research portfolio further covers the structural analysis of tubulin-complexes with various modulatory proteins. As part of the EU-funded Innovative Training Network TubInTrain https://www.tubintrain.eu, we study the role of microtubules in neurotoxicity and neurodegenerative disorders. In particular, we investigate different strategies for tuning tubulin/MTs dynamics and interactions with selected proteins and ligands at the atomic level, aiming at providing new relevant indications for the future design of effective drugs or novel therapeutic interventions.

2019

Horizon 2020 MSCA-ITN EJD Grant TubInTrain (www.tubintrain.eu).

The TubInTrain network has participants from six European countries and encompasses ten academic groups and ten companies committed to creating an outstanding training program for thirteen early stage researchers (ESRs) to elucidate the mechanisms of neurodegeneration associated to microtubules structure and dynamics.

• A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin. Menchon G, Prota AE, Lucena-Agell D, Bucher P, Jansen R, Irschik H, Muller R, Paterson I, Diaz JF, Altmann KH, Steinmetz MO
  NATURE COMMUNICATIONS 9, 2106 (2018).
  DOI: 10.1038/S41467-018-04535-8
• High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design. Bueno O, Estevez Gallego J, Martins S, Prota AE, Gago F, Gomez-SanJuan A, Camarasa MJ, Barasoain I, Steinmetz MO, Diaz JF, Perez-Perez MJ, Liekens S, Priego EM
  Scientific Reports 8, 4242 (2018).
• Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton Steinmetz Michel O, Prota Andrea E
  TRENDS IN CELL BIOLOGY 28, 776 (2018).
  DOI: 10.1016/j.tcb.2018.05.001
• Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure Dohle W, Jourdan Fabrice L, Menchon G, Prota Andrea E, Foster Paul A, Mannion P, Hamel E, Thomas Mark P, Kasprzyk Philip G, Ferrandis E, Steinmetz Michel O, Leese Mathew P, Potter Barry VL
  JOURNAL OF MEDICINAL CHEMISTRY , acs.jmedchem.7b01474 (2018).
  DOI: 10.1021/acs.jmedchem.7b01474
• Structural Basis of Formation of the Microtubule Minus-End-Regulating CAMSAP-Katanin Complex Jiang K, Faltova L, Hua S, Capitani G, Prota Andrea E, Landgraf C, Volkmer R, Kammerer Richard A, Steinmetz Michel O, Akhmanova A
  STRUCTURE -, S0969212617304422 (2018).
  DOI: 10.1016/j.str.2017.12.017
• Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents. Brindisi M, Ulivieri C, Alfano G, Gemma S, de Asis Balaguer F, Khan T, Grillo A, Chemi G, Menchon G, Prota AE, Olieric N, Lucena-Agell D, Barasoain I, Diaz JF, Nebbioso A, Conte M, Lopresti L, Magnano S, Amet R, Kinsella P, Zisterer DM, Ibrahim O, OSullivan J, Morbidelli L, Spaccapelo R, Baldari C, Butini S, Novellino E, Campiani G, Altucci L, Steinmetz MO, Brogi S
  EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 162, 290 (2018).
• 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 N, Collins H, Eastman H, Barrow Andrew S, Lim K, Kam T, Smith Brian J, Duivenvoorden Hendrika M, Parker Belinda S, Bradshaw Tracey D, Steinmetz Michel O, Moses John E
  Scientific Reports 8, 10617 (2018).
  DOI: 10.1038/s41598-018-28880-2

• Antivascular and antitumor properties of the tubulin-binding chalcone TUB091 Canela M, Noppen S, Bueno O, Prota A, Bargsten K, Sáez-Calvo G, Jimeno M, Benkheil M, Ribatti D, Velázquez S, Camarasa M, Díaz JFernando, Steinmetz MO, Priego E, Pérez-Pérez M, Liekens S
  ONCOTARGET 8, 14325 (2017).
  DOI: 10.18632/oncotarget.9527
• Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent. Jost M, Chen Y, Gilbert LA, Horlbeck MA, Krenning L, Menchon G, Rai A, Cho MY, Stern JJ, Prota AE, Kampmann M, Akhmanova A, Steinmetz MO, Tanenbaum ME, Weissman JS
  MOLECULAR CELL Oct 5;68(1), 210 (2017).
  DOI: 10.1016/j.molcel.2017.09.012
• Deconvolution of Buparlisib?s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention Bohnacker T, Prota AE, Beaufils F, Burke John E, Melone A, Inglis Alison J, Rageot D, Sele Alexander M, Cmiljanovic V, Cmiljanovic N, Bargsten K, Aher A, Akhmanova A, Díaz JFernando, Fabbro D, Zvelebil M, Williams Roger L, Steinmetz MO, Wymann Matthias P
  NATURE COMMUNICATIONS 8, 14683 (2017).
  DOI: 10.1038/ncomms14683
• Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons Weinert T, Olieric N, Cheng R, Brünle S, James D, Ozerov D, Gashi D, Vera L, Marsh M, Jaeger K, Dworkowski F, Panepucci E, Basu S, Skopintsev P, Doré Andrew S, Geng T, Cooke Robert M, Liang M, Prota Andrea E, Panneels V, Nogly P, Ermler U, Schertler G, Hennig M, Steinmetz Michel O, Wang M, Standfuss J
  NATURE COMMUNICATIONS 8, 542 (2017).
  DOI: 10.1038/s41467-017-00630-4
• Short Linear Sequence Motif LxxPTPh Targets Diverse Proteins to Growing Microtubule Ends. Kumar A, Manatschal C, Rai A, Grigoriev I, Degen MS, Jaussi R, Kretzschmar I, Prota AE, Volkmer R, Kammerer RA, Akhmanova A, Steinmetz MO
  STRUCTURE 25, 924 (2017).
  DOI: 10.1016/J.STR.2017.04.010
• Structural Basis of Microtubule Stabilization by Discodermolide Prota Andrea E, Bargsten K, Redondo M, Smith III Amos B, Yang ChiaPing H, McDaid Hayley M, Paterson I, Horwitz Susan B, Díaz J, Steinmetz Michel O
  CHEMBIOCHEM , (2017).
  DOI: 10.1002/cbic.201600696
• Structural Basis of cis- and trans-Combretastatin Binding to Tubulin Gaspari R, Prota Andrea E, Bargsten K, Cavalli A, Steinmetz Michel O
  Chem 2, 102 (2017).
  DOI: 10.1016/j.chempr.2016.12.005
• Structural basis of katanin p60:p80 complex formation Rezabkova L, Jiang K, Capitani G, Prota Andrea E, Akhmanova A, Steinmetz Michel O, Kammerer Richard A
  Scientific Reports 7, 14893 (2017).
  DOI: 10.1038/s41598-017-14194-2
• Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin. Saez-Calvo G, Sharma A, Balaguer FA, Barasoain I, Rodriguez-Salarichs J, Olieric N, Munoz-Hernandez H, Berbis MA, Wendeborn S, Penalva MA, Matesanz R, Canales A, Prota AE, Jimenez-Barbero J, Andreu JM, Lamberth C, Steinmetz MO, Diaz JF
  CELL CHEMICAL BIOLOGY 24, 737 (2017).
  DOI: 10.1016/J.CHEMBIOL.2017.05.016
• Zampanolide Binding to Tubulin Indicates Cross-Talk of Taxane Site with Colchicine and Nucleotide Sites. Field JJ, Pera B, Gallego JE, Calvo E, Rodriguez-Salarichs J, Saez-Calvo G, Zuwerra D, Jordi M, Andreu JM, Prota AE, Menchon G, Miller JH, Altmann KH, Diaz JF
  JOURNAL OF NATURAL PRODUCTS , (2017).
  DOI: 10.1021/acs.jnatprod.7b00704

• Pironetin Binds Covalently to alpha Cys316 and Perturbs a Major Loop and Helix of alpha-Tubulin to Inhibit Microtubule Formation. Prota AE, Setter J, Waight AB, Bargsten K, Murga J, Diaz JF, Steinmetz MO
  JOURNAL OF MOLECULAR BIOLOGY 428, 2981 (2016).
  DOI: 10.1016/J.JMB.2016.06.023
• Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE
  PLOS ONE 11, e0160890 (2016).
  DOI: 10.1371/journal.pone.0160890
• Structural Determinants of the Dictyostatin Chemotype for Tubulin Binding Affinity and Antitumor Activity Against Taxane- and Epothilone-Resistant Cancer Cells Trigili C, Barasoain I, Sánchez-Murcia Pedro A, Bargsten K, Redondo-Horcajo M, Nogales A, Gardner Nicola M, Meyer A, Naylor Guy J, Gómez-Rubio E, Gago F, Steinmetz Michel O, Paterson I, Prota Andrea E, Díaz JFernando
  ACS Omega 1, 1192 (2016).
  DOI: 10.1021/acsomega.6b00317
• Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes Doodhi Harinath, Prota Andrea E, Rodriguez-Garcia Ruddi, Xiao Hui, Custar Daniel W, Bargsten Katja, Katrukha Eugene A, Hilbert Manuel, Hua Shasha, Jiang Kai, Grigoriev Ilya, Yang ChiaPing H, Cox David, Horwitz Susan Band, Kapitein Lukas C, Akhmanova Anna, Steinmetz Michel O
  CURRENT BIOLOGY 26, 1713-1721 (2016).
  DOI: 10.1016/j.cub.2016.04.053
• The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity Wieczorek Michal, Tcherkezian Joseph, Bernier Cynthia, Prota AE, Chaaban Sami, Rolland Yanneve, Godbout Claude, Hancock Mark A, Arezzo Joseph C, Ocal Ozhan, Rocha Cecilia, Olieric N, Hall Anita, Ding Hui, Bramoulle Alexandre, Annis Matthew G, Zogopoulos George, Harran Patrick G, Wilkie Thomas M, Brekken Rolf A, Siegel Peter M, Steinmetz MO, Shore Gordon C, Brouhard Gary J, Roulston Anne
  SCIENCE TRANSLATIONAL MEDICINE 8, 365ra159 (2016).
  DOI: 10.1126/scitranslmed.aag1093

• Fast native-SAD phasing for routine macromolecular structure determination Weinert Tobias, Olieric Vincent, Waltersperger Sandro, Panepucci Ezequiel, Chen Lirong, Zhang Hua, Zhou Dayong, Rose John, Ebihara Akio, Kuramitsu Seiki, Li Dianfan, Howe Nicole, Schnapp Gisela, Pautsch Alexander, Bargsten Katja, Prota Andrea E, Surana Parag, Kottur Jithesh, Nair Deepak T, Basilico Federica, Cecatiello Valentina, Pasqualato Sebastiano, Boland Andreas, Weichenrieder Oliver, Wang Bi-Cheng, Steinmetz Michel O, Caffrey Martin, Wang Meitian
  NATURE METHODS 12, 131-U163 (2015).
  DOI: 10.1038/nmeth.3211
• Fast native-SAD phasing for routine macromolecular structure determination (vol 12, pg 131, 2015) Weinert Tobias, Olieric Vincent, Waltersperger Sandro, Panepucci Ezequiel, Chen Lirong, Zhang Hua, Zhou Dayong, Rose John, Ebihara Akio, Kuramitsu Seiki, Li Dianfan, Howe Nicole, Schnapp Gisela, Pautsch Alexander, Bargsten Katja, Prota Andrea E, Surana Parag, Kottur Jithesh, Nair Deepak T, Basilico Federica, Cecatiello Valentina, Pasqualato Sebastiano, Boland Andreas, Weichenrieder Oliver, Wang BiCheng, Steinmetz Michel O, Caffrey Martin, Wang Meitian
  NATURE METHODS 12, 692-692 (2015).

• A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs Prota Andrea E, Bargsten Katja, Fernando Diaz J, Marsh May, Cuevas Carmen, Liniger Marc, Neuhaus Christian, Andreu Jose M, Altmann Karl-Heinz, Steinmetz Michel O
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111, 13817-13821 (2014).
  DOI: 10.1073/pnas.1408124111
• Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A Prota Andrea E, Bargsten Katja, Northcote Peter T, Marsh May, Altmann Karl-Heinz, Miller John H, Fernando Diaz Jose, Steinmetz Michel O
  ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 53, 1621-1625 (2014).
  DOI: 10.1002/anie.201307749
• The Novel Microtubule-Destabilizing Drug BAL27862 Binds to the Colchicine Site of Tubulin with Distinct Effects on Microtubule Organization Prota Andrea E, Danel Franck, Bachmann Felix, Bargsten Katja, Buey Ruben M, Pohlmann Jens, Reinelt Stefan, Lane Heidi, Steinmetz Michel O
  JOURNAL OF MOLECULAR BIOLOGY 426, 1848-1860 (2014).
  DOI: 10.1016/j.jmb.2014.02.005

• Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents Prota Andrea E, Bargsten Katja, Zurwerra Didier, Field Jessica J, Fernando Diaz Jose, Altmann Karl-Heinz, Steinmetz Michel O
  SCIENCE 339, 587-590 (2013).
  DOI: 10.1126/science.1230582
• Structural Basis for Universal Corrinoid Recognition by the Cobalamin Transport Protein Haptocorrin Furger E, Frei DC, Schibli R, Fischer E, Prota AE
  JOURNAL OF BIOLOGICAL CHEMISTRY 288, 25466 (2013).
• Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation Leppanen Veli-Matti, Tvorogov Denis, Kisko Kaisa, Prota Andrea E, Jeltsch Michael, Anisimov Andrey, Markovic-Mueller Sandra, Stuttfeld Edward, Goldie Kenneth N, Ballmer-Hofer Kurt, Alitalo Kari
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110, 12960-12965 (2013).
  DOI: 10.1073/pnas.1301415110
• Structural basis of tubulin tyrosination by tubulin tyrosine ligase Prota Andrea E, Magiera Maria M, Kuijpers Marijn, Bargsten Katja, Frey Daniel, Wieser Mara, Jaussi Rolf, Hoogenraad Casper C, Kammerer Richard A, Janke Carsten, Steinmetz Michel O
  JOURNAL OF CELL BIOLOGY 200, 259-270 (2013).
  DOI: 10.1083/jcb.201211017

• Structural determinants of growth factor binding and specificity by VEGF receptor 2 Leppanen VM, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K, Alitalo K
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107, 2425 (2010).
  DOI: 10.1073/pnas.0914318107
• Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling Grunewald FS, Prota AE, Giese A, Ballmer-Hofer K
  BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 1804, 567 (2010).
  DOI: 10.1016/j.bbapap.2009.09.002

• Mutational studies of Pa-AGOG DNA glycosylase from the hyperthermophilic crenarchaeon Pyrobaculum aerophilum Lingaraju Gondichatnahalli M, Prota AE, Winkler FK
  DNA REPAIR 8, 857 (2009).
  DOI: 10.1016/j.dnarep.2009.03.009

• Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR Cebe-Suarez P, Grunewald FS, Jaussi R, Li XJ, Claesson-Welsh L, Spillmann D, Mercer AA, Prota AE, Ballmer-Hofer K
  FASEB JOURNAL 22, 3078 (2008).
  DOI: 10.1096/fj.08-107219

• Crystal structure of the Orf virus NZ2 variant of vascular endothelial growth factor-E - Implications for receptor specificity Pieren M, Prota AE, Ruch C, Kostrewa D, Wagner A, Biedermann K, Winkler FK, Ballmer-Hofer K
  JOURNAL OF BIOLOGICAL CHEMISTRY 281, 19578 (2006).
  DOI: 10.1074/jbc.M601842200
• Structure determination of VEGF-E by sulfur SAD Wagner A, Pieren M, Schulze-Briese C, Ballmer-Hofer K, Prota AE
  ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY 62, 1430 (2006).
  DOI: 10.1107/S0907444906036742

• A DNA Glycosylase from Pyrobaculum aerophilum with an 8-Oxoguanine Binding Mode and a Noncanonical Helix-Hairpin-Helix Structure Lingaraju Gondichatnahalli M, Sartori Alessandro A, Kostrewa D, Prota Andrea E, Jiricny J, Winkler FK
  STRUCTURE 13, 87 (2005).
  DOI: 10.1016/j.str.2004.10.011

• A Molecular Dynamics Study of Reovirus Attachment Protein ?1 Reveals Conformational Changes in ?1 Structure Cavalli A, Prota AE, Stehle T, Dermody Terence S, Recanatini M, Folkers G, Scapozza L
  BIOPHYSICAL JOURNAL 86, 3423 (2004).
  DOI: 10.1529/biophysj.103.030825

• Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding Prota AE, Campbell JA, Schelling P, Forrest JC, Watson MJ, Peters TR, Aurrand-Lions M, Imhof BA, Dermody TS, Stehle T
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 100, 5366 (2003).
  DOI: 10.1073/pnas.0937718100

• The crystal structure of human CD21: Implications for Epstein-Barr virus and C3d binding Prota AE, Sage DR, Stehle T, Fingeroth JD
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 99, 10641 (2002).
  DOI: 10.1073/pnas.162360499

• Crystal structure of reovirus attachment protein sigma1 reveals evolutionary relationship to adenovirus fiber JD Chappell, AE Prota, TS Dermody and T Stehle
  EMBO J 21, 1-11 (2002).
  DOI: 10.1093/emboj/21.1.1

• Nucleoside binding site of herpes simplex type 1 thymidine kinase analyzed by x-ray crystallography J Vogt, R Perozzo, A Pautsch, A Prota, P Schelling, B Pilger, G Folkers, L Scapozza and GE Schulz
  Proteins 41, 545-553 (2000).
• Extended substrate acceptance of herpes simplex virus type 1 thymidine kinase: A new chance for gene and antiviral therapy L Scapozza, P Ballmer, R Johner, R Perozzo, B Pilger, P Pospisil, A Prota, P Schelling, L Spadola, C Wurth and G Folkers
  CHIMIA International Journal for Chemistry 54, 663-668 (2000).
• Kinetics and crystal structure of the wild-type and the engineered y101f mutant of herpes simplex virus type 1 thymidine kinase interacting with (north)-methanocarba-thymidine A Prota, J Vogt, B Pilger, R Perozzo, C Wurth, VE Marquez, P Russ, GE Schulz, G Folkers and L Scapozza
  Biochemistry 39, 9597-9603 (2000).

• Modelling of guanine-derivative--protein interaction complexes as a basis of drug design G Folkers, A Prota and A Merz
  Farmaco 50, 449-454 (1995).