Seminarios

A large part of the eukaryotic proteome is formed by intrinsically disordered proteins (IDPs). IDPs take advantage of their lack of stable tertiary fold to perform multitude of cellular processes.

Remarkably, IDPs show structural plasticity and can modulate the ensemble of conformations upon certain stimuli, in a process which may lead to the formation of stable ordered structures. These fibrillar, amyloid structures can play key roles in functional processes, but can also be related to the onset and progress of protein diseases1, which have tremendous socio-economic impact. Indeed, the critical toxic species in over 40 human diseases are misfolded proteins2, which may spur aberrant folds prompting protein toxicity and cell death. Intense research over the last decades has enabled the understanding of many crucial molecular processes that determine the progress of these diseases. However, we lack mechanistic insights into the early misfolding changes that trigger protein toxicity, which appear to happen within confined environments, such as biomolecular condensates formed by liquid-liquid phase separation (LLPS)1,3. In this talk, I will review the current knowledge on the structural basis of pathogenic amyloidosis and why this is highly relevant for the development of active biomarkers or therapeutics for the diseases. I will explain why Nuclear Magnetic Resonance (NMR) spectroscopy is the only high-resolution structural technique that enables the study of IDPs’ properties in disease. Lastly, I will focus on the discoveries that we have achieved by NMR on toxic proteins and present a perspective of what are the main bottlenecks currently faced and the lines of research that will be launched in the near future.

  1. Hervás, R., Oroz, J. (2020) Mechanistic insights into the role of molecular chaperones in protein misfolding diseases: From molecular recognition to amyloid disassembly. Int. J. Molec. Sci. 21: 9186.
  2. Chiti, F., Dobson, C. M. (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem. 86: 27-68.
  3. Bolognesi, B., et al. (2019) The mutational landscape of a prion-like domain. Nat. Commun. 10: 4162.

Fecha del seminario: 14/04/2021 12:00

Ponente del seminario: Javier Oroz

Abstract