Professor Paula da Fonseca

  • Professor of Cryo-electron Microscopy (Institute of Molecular Cell & Systems Biology)

Biography

Paula graduated in Biochemistry at the Faculdade de Ciências, Universidade de Lisboa, Portugal, and obtained her PhD in Biochemistry by the University of London, UK, for her studies at the Imperial College of Science, Technology and Medicine. She held postdoctoral positions in London, at the Imperial College School of Medicine and at the Institute of Cancer Research. In 2013 Paula moved to Cambridge, UK, to start her own research group at the MRC Laboratory of Molecular Biology. In April 2020 she relocated her group to the University of Glasgow, where she holds the position of Professor of Cryo-Electron Microscopy. Since her PhD, Paula has been studying regulatory protein complexes primarily by electron microscopy-based methods.  Her current work focuses on studying the structure and function of eukaryotic proteasome complexes, with emphasis on fully understanding the different human variants. Additionally, she is investigating the use of high resolution cryo-EM in the development of new therapeutic drugs. Within this context, her cryo-EM work contributed to the validation of the Plasmodium proteasome as a potential target for antimalarials and the structural information provided is now being harnessed in the development of Plasmodium proteasome inhibitors with improved specificity and potency.


Research interests

Currently our main aim is to fully characterise the human proteasome. All cells depend on continuous protein turnover. The proteasome is the complex responsible for the degradation of most proteins in eukaryotic cells including those that are damaged or not properly folded, which would otherwise accumulate with serious detrimental consequences. Additionally, the proteasome also degrades specific proteins the removal of which signals for fundamental processes including cell cycle progression, DNA repair and apoptosis onset. The canonical proteasome complex, the 26S proteasome, is an ATP-dependent protease that degrades protein substrates that are specifically tagged by ubiquitin signals. However, there are other proteasome variants in higher eukaryotes, including those specifically involved in the immune response. Although the proteasome is essential in all eukaryotic cells, and a well-recognised therapeutic target for varied conditions including cancer and inflammatory diseases, its detailed functional mechanisms and regulation are still not fully described.

Recently we improved the preparation of proteasome samples, to allow us to fully characterise the human proteasome as a family of distinct functional variants. Our high resolution cryo-electron microscopy (cryo-EM) analysis of proteasome complexes also served to demonstrate the advantages of cryo-EM to study protein-ligand interactions to assist in drug discovery and development, including in contributing to the validation of the Plasmodium falciparum proteasome as a potential antimalarial target and providing a molecular basis for improved proteasome inhibitor specificity. We are now building on these achievements to provide an unambiguous description of the proteasome’s function and regulation, and to contribute to improve and effectively extend its targeting to varied therapeutic usages.


Publications

List by: Type | Date

Jump to: 2019 | 2017 | 2016 | 2015
Number of items: 6.

2019

Toste Rêgo, A. and da Fonseca, P. C.A. (2019) Characterization of fully recombinant human 20S and 20S-PA200 proteasome complexes. Molecular Cell, 76(1), 138-147.e5. (doi: 10.1016/j.molcel.2019.07.014) (PMID:31473102) (PMCID:PMC6863390)

Blackman, M. J. et al. (2019) Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathogens, 15(6), e1007722. (doi: 10.1371/journal.ppat.1007722) (PMID:31170268) (PMCID:PMC6553790)

2017

Morris, E. P. and da Fonseca, P. C.A. (2017) High-resolution cryo-EM proteasome structures in drug development. Acta Crystallographica. Section D: Structural Biology, 73(6), pp. 522-533. (doi: 10.1107/S2059798317007021) (PMID:28580914) (PMCID:PMC5458494)

2016

Li, H., Bogyo, M. and da Fonseca, P. C.A. (2016) The cryo-EM structure of thePlasmodium falciparum20S proteasome and its use in the fight against malaria. FEBS Journal, 283(23), pp. 4238-4243. (doi: 10.1111/febs.13780) (PMID:27286897) (PMCID:PMC5140733)

Li, H., O’Donoghue, A. J., van der Linden, W. A., Xie, S. C., Yoo, E., Foe, I. T., Tilley, L., Craik, C. S., da Fonseca, P. C.A. and Bogyo, M. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature, 530(7589), pp. 233-236. (doi: 10.1038/nature16936) (PMID:26863983) (PMCID:PMC4755332)

2015

da Fonseca, P. C.A. and Morris, E. P. (2015) Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core. Nature Communications, 6(1), 7573. (doi: 10.1038/ncomms8573) (PMID:26133119) (PMCID:PMC4506541)

This list was generated on Thu Jul 9 09:57:01 2020 BST.
Jump to: Articles
Number of items: 6.

Articles

Toste Rêgo, A. and da Fonseca, P. C.A. (2019) Characterization of fully recombinant human 20S and 20S-PA200 proteasome complexes. Molecular Cell, 76(1), 138-147.e5. (doi: 10.1016/j.molcel.2019.07.014) (PMID:31473102) (PMCID:PMC6863390)

Blackman, M. J. et al. (2019) Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathogens, 15(6), e1007722. (doi: 10.1371/journal.ppat.1007722) (PMID:31170268) (PMCID:PMC6553790)

Morris, E. P. and da Fonseca, P. C.A. (2017) High-resolution cryo-EM proteasome structures in drug development. Acta Crystallographica. Section D: Structural Biology, 73(6), pp. 522-533. (doi: 10.1107/S2059798317007021) (PMID:28580914) (PMCID:PMC5458494)

Li, H., Bogyo, M. and da Fonseca, P. C.A. (2016) The cryo-EM structure of thePlasmodium falciparum20S proteasome and its use in the fight against malaria. FEBS Journal, 283(23), pp. 4238-4243. (doi: 10.1111/febs.13780) (PMID:27286897) (PMCID:PMC5140733)

Li, H., O’Donoghue, A. J., van der Linden, W. A., Xie, S. C., Yoo, E., Foe, I. T., Tilley, L., Craik, C. S., da Fonseca, P. C.A. and Bogyo, M. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature, 530(7589), pp. 233-236. (doi: 10.1038/nature16936) (PMID:26863983) (PMCID:PMC4755332)

da Fonseca, P. C.A. and Morris, E. P. (2015) Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core. Nature Communications, 6(1), 7573. (doi: 10.1038/ncomms8573) (PMID:26133119) (PMCID:PMC4506541)

This list was generated on Thu Jul 9 09:57:01 2020 BST.