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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.

Projects

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.

Lab people

Principal investigator

Bernat Crosas obtained his degree in Biology at University of Barcelona (UB), and his PhD at the university autonomous of Barcelona (UAB), on oxidoreductases active with ethanol and retinoids. In 2001, he joined Dr. Finley lab, at the Department of Cell Biology of Harvard Medical School, working on proteasome regulation. In 2005, he obtained a Ramon y Cajal contract to join the IBMB, at Dr. Thomson lab, at the IBMB, where he developed projects on regulation of proteasome substrate receptors.

In 2009, he obtained a CSIC scientist researcher position. His lab is focused on uncovering novel levels of regulation of proteasome function and on the development of new drug, in collaboration with the Research Unit of Bioactive Molecules (RUBAM), at the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC).

Past students

Hector Carneros

Postdoctoral Research Associate

Regulation of the proteasome

Anne Bichmann

PhD Student

Regulation of the proteasome

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. Scientific Reports 6:29232. doi: 10.1038/srep29232


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. Journal of Biological Chemistry 291(4):1664-75. doi: 10.1074/jbc.M115.698662


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. Biochemical Journal. 472(3):353-365. doi: 10.1042/BJ20150609


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. Biochemical Journal. 469(3):455-467. doi: 10.1042/BJ20141571


Crosas. B. (2014). Deubiquitinating enzyme inhibitor and their potencial in cance therapy. Current Cancer Drug Targets 14(6), 506-516. doi: 10.2174/1568009614666140725090620

All 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. Scientific Reports 6:29232. doi: 10.1038/srep29232


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. Journal of Biological Chemistry 291(4):1664-75. doi: 10.1074/jbc.M115.698662


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. Biochemical Journal. 472(3):353-365. doi: 10.1042/BJ20150609


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. Biochemical Journal. 469(3):455-467. doi: 10.1042/BJ20141571


Crosas. B. (2014). Deubiquitinating enzyme inhibitor and their potencial in cance therapy. Current Cancer Drug Targets 14(6), 506-516. doi: 10.2174/1568009614666140725090620


Zuin, A., Isasa, M., Crosas, B. (2014) “Ubiquitin signaling: extreme conservation as a source of Diversity” Cells, 3, 690-701. doi: 10.3390/cells3030690


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. Journal of Biological Chemistry 288, 4704-4714. doi: 10.1074/jbc.M112.426593


Isasa, M., Zuin, A., and Crosas, B. (2012) “Integration of multiple ubiquitin signals in proteasome regulation”. Methods in Molecular Biology 910, 337-70. doi: 10.1007/978-1-61779-965-5_15


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. doi: 10.1016/j.molcel.2010.05.001


Katz., E.J., Isasa, M., and Crosas, B* (2010) A new map to understand deubiquitination. Biochemical Society Transactions, 38(Pt 1): 21-8. doi: 10.1042/BST0380021


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. doi: 10.1042/BST0380001


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. doi: 10.1016/j.cell.2006.09.051


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) Deubiquitinating Enzyme Ubp6 Functions Noncatalytically to Delay Proteasomal Degradation. Cell, 127, 99-111. doi: 10.1016/j.cell.2006.07.038


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. Journal of Biological Chemistry, 280, 20365-20374. doi: 10.1074/jbc.M414356200


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. Nature Structural & Molecular Biology, 12, 294-303. doi: 10.1038/nsmb914


JanseD.M., Crosas, B., Finley, D., Church, G.M. (2004) Localization to the Proteasome is Sufficient for Degradation. Journal of Biologial Chemistry. 279 (20): 21415-21420. doi: 10.1074/jbc.M402954200


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. Biochemical Journal 373 (3): 973-979. doi: 10.1042/bj20021818


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. Molecular Cell 10 (3): 495-507. doi: 10.1016/S1097-2765(02)00638-X


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. Cellular and Molecular Life Sciences 58 (9):1323-1326. doi: 10.1007/PL00000942


Crosas, B., Cederlund, E., Torres, D., Farrés, J., Jörnvall, H. and Parés, X. (2001) A vertebrate aldo­keto reductase active with retinoids and ethanol. Journal of Biological Chemistry 276 (22): 19132-19140. doi: 10.1074/jbc.M010478200


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. Chemico-Biological Interactions 130-132, 435-444. doi: 10.1016/S0009-2797(00)00288-X


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. Journal of Biological Chemistry 275 (33): 25180-25187. doi: 10.1074/jbc.M910040199


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. doi: 10.1053/he.2000.5978


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. Journal of Biological Chemistry 274 (53): 37869-37875. doi: 10.1074/jbc.274.53.37869


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. Journal of Biological Chemistry 274 (37): 26021-26026. doi: 10.1074/jbc.274.37.26021


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. Advances in Experimental Medicine and Biology 463: 343-350. doi: 10.1007/978-1-4615-4735-8_42


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. Advances in Experimental Medicine and Biology 372: 331-339. doi: 10.1007/978-1-4615-1965-2_40


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. European Journal of Biochemistry 224, 549-557. doi: 10.1111/j.1432-1033.1994.00549.x

Project funding

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

Services

Production of recombinant proteins by means of prokaryotic and eukaryotic systems. Design of cloning, expressión and purification.
Up to 50 mg, 2.800 euros (+taxes)

Vacancies/Jobs

We offer a PhD student position granted by the Spanish Ministry of Science and Innovation.  Applications will be considered ASAP.

Lab corner

General Links

  • Inproteolys network INPROTEOLYS – Proteasome group  
  • Yeast genome database  SGD
  • NCBI – PubMed PUBMED  
  • Euroscarf database EUROSCARF 
  • European Bioinformatics Institute EBI 
  • Sequence Manipulation SMS 
  • Links – documents

Press Notes

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

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