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Bernat Crosas: Regulation of the proteasome

Basic and applied research focused on proteasome degradation processes

Lab Presentation

The goal of the lab is to examine novel levels of regulation of the proteasome pathway focusing on the mechanisms that control proteasome function and its interaction with protein substrates. Our ongoing studies pursue basic and translational research areas. Our objective is to characterize the regulatory interactions that control the process of protein degradation in the proteasome. We also aim to identify novel ubiquitin pathway substrates by means of an optimized biochemical fractionation of ubiquitin conjugates. The development of these projects will uncover mechanisms of action of the proteasome, which will be integrated in the comprehension of the role of the proteasome in cell physiology and molecular pathology. One of our priorities will be to reveal novel targets in the proteasome pathway for the design of drug therapies. The use of S. cerevisiae, the reference model in the ubiquitin-proteasome system, will allow us to address simultaneously biochemical, genetic, molecular and cell biology approaches in feasible time frames.

Research Lines

To study the proteasome mechanism, focusing on the role of the regulatory particle.
We are interested in understanding how the proteasome processes substrates delivered from multiple cellular pathways, in terms of selectivity, priority and homeostatic feedback. The regulatory particle of the proteasome is a functional network of interacting subunits and associated factors which define several levels of control of the proteolytic pathway. Our aim is to uncover this network.
To define the physiological scope of the ubiquitin-proteasome system.
We are interested in characterizing novel substrates of the system. Inversely, we are also interested in developing a method of conditional degradation by ubiquitin independent approaches, in order to create artificial substrates of the proteasome.
Bernat Crosas Navarro

Principal Investigator



Past students

list of selected publications
  • Bijlmakers, M.J., Teixeira, J.,M., Boer, R., Mayzel, M., Puig-Sàrries, P., Karlsson, G., Coll, M., Pons, M., Crosas B. (2016) A C2HC zinc finger is essential for the RING-E2 interaction of the ubiquitin ligase RNF125. Sci. Rep. 6:29232.
  • Isasa, M., Suñer, C., Díaz, M., Puig-Sàrries, P., Zuin, A., Bichmann, A, Gygi, S,P,, Rebollo, E., Crosas, B. (2016) Cold Temperature Induces the Reprogramming of Proteolytic Pathways in Yeast. J. Biol. Chem. 291(4):1664-75.
  • Zuin, A., Bichmann, A., Isasa, M., Puig-Sàrries, P., Díaz, L.M., Crosas, B. (2015) Rpn10 monoubiquitination orchestrates the association of the ubiquilin-type DSK2 receptor with the proteasome. Biochem. J. 472(3):353-365.
  • Puig-Sàrries, P., Bijlmakers, M.J., Zuin, A., Bichmann, A., Pons, M., Crosas, B. (2015) An intrinsically disordered region of RPN10 plays a key role in restricting ubiquitin chain elongation in RPN10 monoubiquitination. Biochem J. 469(3):455-467.
  • Crosas. B. (2014) “Deubiquitinating enzyme inhibitor and their potencial in cance therapy”  Curr. Cancer Drug Targets. 14, 506-516.        
  • Zuin, A., Isasa, M., Crosas, B. (2014) “Ubiquitin signaling: extreme conservation as a source of Diversity” Cells, 3, 690-701.
  • Hernández-Ortega S, Bru S, Ricco N, Ramírez S, Casals N, Jiménez J, Isasa M, Crosas B, Clotet J. (2013) Defective in mitotic arrest 1 (Dma1) ubiquitin ligase controls G1 cyclin degradation. J. Biol. Chem. 288, 4704-4714.
  • Isasa, M., Zuin, A., and Crosas, B. (2012) Integration of multiple ubiquitin signals in proteasome regulation”. Methods Mol. Biol. 910, 337-70.
  • Isasa, M., Katz., E.J., Kim, W., Yugo, V., González., S., Kirkpatrick, D.S., Thomson, T.M., Finley., S., Gygi, S.P. and Crosas, B*. (2010) Monoubiquitination of rpn10 regulates substrate recruitment to the proteasome. Molecular Cell, 38(5), 733-745. Cover and preview.
  • Katz., E.J., Isasa, M., and Crosas, B* (2010) A new map to understand deubiquitination.  Biochemical Society Transactions, 38(Pt 1): 21-8.
  • Crosas, B.*, Farràs, R., Marfany, G., Rodríguez, M. and Thomson, T.M*. Searching for the boundaries: unlimited expansion of ubiquitin and ubiquitin-like signals in multiple cellular functions (2010) Biochemical Society Transactions, 38(Pt 1): 1-5.
  • Crosas, B., Hanna, J., Kirkpatrick, D.S., Zang, P.,Tone, Y., Hathaway, N.A., Buecker, C., Leggett, D.S., Schmidt, M., King, R.W., Gygi, S.P. and Finley, D. (2006) Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 127, 1401-1413.
  • Hanna, J., Hathaway, N.A., Tone, Y., Crosas, B., Elsasser, S., Kirkpatrick, D.S. Leggett, D.S., Gygi, S.P., King, R.W., and Finley, D. (2006) A Deubiquitinating Enzyme Functions Non-catalytically to Inhibit the Proteasome. Cell, 127, 99-111.
  • Shang, F., Deng, G., Liu, Q., Guo, W., Haas, A.L., Crosas, B., Finley, D., Taylor, A. (2005) LYS-6-modified ubiquitin inhibits ubiquitin-dependent protein degradation. J. Biol. Chem., 280, 20365-20374.
  • Schmidt, M., Haas, W., Crosas., B., Santamaria, P.G., Gygi, S.P., Walz. A, Finley, D. (2005) The HEAT repeat protein Blm10 regulates the yeast proteasome by capping the core particle. Nat. Struct. Mol. Biol, 12, 294-303.
  • JanseD.M., Crosas, B., Finley, D., Church, G.M. (2004) Localization to the Proteasome is Sufficient for Degradation. J. Biol. Chem. 279 (20): 21415-21420.
  • Crosas, B., Hyndman, D.J., Gallego, O., Martras, S., Parés, X., Flynn, T.G., Farrés, J. (2003) Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism. Biochem. J. 373 (3): 973-979.
  •  Leggett, D.S., Hanna, J., Borodovsky, A., Crosas, B., Schmidt, M., Baker, R.T., Walz, T., Ploegh, H., Finley, D. (2002) Multiple associated proteins regulate proteasome structure and function. Mol. Cell 10 (3): 495-507. 
  •  Hirschberg, D., Cederlund, E., Crosas, B., Jonsson, A., Tryggvason, S., Farrés, J., Parés, X., Bergman, T., Jornvall, H. (2001) N-terminal acetylation in a third protein family of vertebrate alcohol dehydrogenase/retinal reductase found through a 'proteomics' approach in enzyme characterization. Cell. Mol. Life Sci. 58 (9):1323-1326.
  • Crosas, B., Cederlund, E., Torres, D., Farrés, J., Jörnvall, H. and Parés, X. (2001) A vertebrate aldo­keto reductase active with retinoids and ethanol. J. Biol. Chem. 276 (22): 19132-19140.
  • Allali-Hassani, A., Crosas, B., Martínez, S.E., Martras, S., Persson, B., Jörnvall, H., Parés, X. and Farrés, J. (2001) Kinetic effects of a single-amino acid mutation in a highly variable loop (residues 114 to 120) of class IV ADH. Chem. Biol. Int. 130-132, 435-444.
  • Crosas, B., Allali-Hassani, A., Martínez, S.E., Martras, S., Persson, B., Jörnvall, H., Parés, X. and Farrés, J. (2000) Molecular basis for differential substrate specificity in class IV alcohol dehydrogenase: A conserved function in retinoid metabolism but not in ethanol oxidation. J. Biol. Chem. 275 (33): 25180-25187.
  • Borràs, E., Coutelle, C., Rosell, A., Fernàndez-Muixí, F., Broch, M., Crosas, B., Hjelmqvist, L., Lorenzo, A., Gutiérrez, C., Santos, M., Szczepanek, M., Heilig, M., Quattrocchi, P, Farrés, J., Vidal, F., Richart, C., Mach, T., Bogdal, J., Jörnvall, H., Seitz, H. K., Couzigou, P. and Parés, X. (2000) Genetic polymorphisms of alcohol dehydrogenase in Europeans. ADH2 *2 allele decreases the risk for alcoholism and is associated with ADH3 *1. Hepatology 31 (4): 984-989.
  • Fernández, M.R., Biosca, J.A., Torres, D., Crosas, B. and Parés, X. (1999) A double residue substitution in the coenzyme binding site accounts for the different kinetic properties between yeast and human formaldehyde dehydrogenases. J. Biol. Chem. 274 (53): 37869-37875.
  • Peralba, J.M., Cederlund, E., Crosas, B., Moreno, A., Julià, P., Martínez, S.E., Hjelmqvist, L., Persson, B., Farrés, J., Parés, X., Jörnvall, H. (1999) Structural and enzymatic properties of a gastric NAPD(H)-dependent and retinal-active alcohol dehydrogenase. J. Biol. Chem. 274 (37): 26021-26026.
  • Peralba, J.M., Crosas, B., Moreno, A., Martínez, S.E., Julià, P., Farrés, J., Parés, X. (1999) Amphibian alcohol dehydrogenase. Purification and characterization of classes I and III from Rana perezi. Adv. Exp. Med. Biol. 463: 343-350.
  • Farrés, J., Moreno, A., Crosas, B., Cederlund, E., Peralba, J.M., Allali-Hassani, A., Hjelmqvist, L., Jörnvall, H., Parés, X. (1994) Human and rat class IV alcohol dehydrogenase: correlation of primary structure with enzymatic properties. Adv. Exp. Med. Biol.  372: 331-339.
  • Farrés, J., Moreno, A., Crosas, B., Peralba, J.M., Allali-Hassani, A., Hjelmqvist, L., Jörnvall, H. and Parés, X. (1994) Alcohol dehydrogenase of class IV (ss-ADH) from human stomach. cDNA sequence and structure/function relationship. Eur. J. Biochem. 224, 549-557.

 

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Characterization of proteasome associated ubiquitin conjugation

  • AGENCY: Programa Nacional de Biología Fundamental, MEC, Spanish Government.
  • PERIOD: 10/2006  -  10/2009
  • IP: Bernat Crosas
     

Functional, structural and genetic characterization of the proteasome associated ubiquitin conjugation. study of poly-ubiquitin signal and its relevance  in molecular pathology

  • AGENCY: MEC, Spanish Government
  • PERIOD: 7/2005  -  7/2010mbc(
  • IP: Bernat Crosas
     

Characterization of novel levels of proteasome regulation

  • AGENCY: Programa Nacional de Biología Fundamental, MEC, Spanish Government.
  • PERIOD: 10/2009  -  10/2012
  • IP: Bernat Crosas
     

Characterization of proteasome regulation and its implications in physiology and molecular pathology

  • AGENCY: Programa Nacional de Biología Fundamental, MINEC, Spanish Government.
  • PERIOD: 1/2013  -  2/2016
  • IP: Bernat Crosas

Purification of proteins from yeast. Design of cloning, expession and protein purification (up to 50 mg).............2400 euros (+IVA)

GENERAL LINKS 

PRESS NOTES

  • TRENDS IN CELL BIOLOGY: "To degrade or to release..." by D.A. Kraut, S. Prakash and A. Matouschek  PUBMED LINK  PDF LINK
  • CSIC: "Se descubre un nuevo mecanismo...."  PDF
  • DIARIO MÉDICO: "Identificado un nuevo..." LINK PDF
  • GACETA MÉDICA: "Nuevos datos sobre la vía ubicuitina-proteasoma..."  PDF, p. 19
  • EL PAÍS: "Una investigación..." LINK 
  • LA VANGUARDIA: "Un equipo de científicos..." LINK

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