Title: Structure and Function of Cell Regulatory Protein Complexes
Funder: Medical Research Council

Abstract: Our work focus on determining the structure and function of cell regulatory protein complexes primarily by electron cryo-microscopy (cryo-EM) based methods. Cell homeostasis is critically regulated by highly specialised macromolecular protein complexes that accurately coordinate specific signals both in time and intracellular location. Deregulation of the function of such complexes is associated with a wide range of medical conditions including cancer. By achieving an understanding of the structural organisation and functional mechanisms of protein complexes critical for cellular function, our work provides a strong framework to understand how the deregulation of these complexes results in disease and should allow the identification of how they can be specifically modulated as therapeutic targets. The latest revolution in the field of cryo-EM has made it suitable to determine protein structures at resolutions that until recently would only be attainable by X-ray crystallography or NMR methods. High resolution cryo-EM has the advantages of allowing the analysis of proteins maintained closer to physiological conditions and also requires significantly smaller amounts of purified protein than normally needed for other methods of protein structure determination. Our work relies on the state-of-the-art electron microscopy facility at the MRC Laboratory of Molecular Biology and the production of high quality samples, combined with their biophysical characterisation to facilitate the interpretation of the structural maps obtained, as required. Currently we aim at fully understanding the molecular mechanisms of the mammalian 26S proteasome. The proteasome is a large ATP dependent protease complex, formed by at least 32 individual subunits, essential in all eukaryotes. Apart from its role in general proteostasis, the proteasome is responsible for the highly regulated degradation of proteins the removal of which signals for fundamental processes such as cell cycle progression and the regulation of gene transcription. The proteasome is a well-established target for cancer therapy since its inhibition induces apoptosis primarily of fast-dividing cells. Second generation proteasome inhibitors are currently used in the treatment of multiple myeloma. Additionally, proteasome inhibition is also being explored as a therapeutic target for other varied conditions such as inflammatory disorders and viral infections, and our recent work contributed to validate the Plasmodium falciparum proteasome as a target for antimalarials. While the overall structural organisation of the 26S proteasome subunits is known, the understanding of its detailed functional mechanisms remains significantly elusive. The complete understanding of these mechanisms is fundamental to clarifying the full role the proteasome plays in the human cells, and how its activity can be efficiently modulated as a therapeutic target, with minimal side effects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE