Clarified the molecular basis of the toxicity of a protein causing an amyloidogenic disease
A recent work, published in Nature Communication and coordinated by Stefano Ricagno and Carlo Camilloni from the Department of Biosciences of the University of Milano, clarifies the biochemical basis of a genetic variant of a protein and its tendency to form toxic aggregates. A mutation in position 76 of beta-2 microglobulin, makes the protein less stable and more prone to aggregation. Patients carrying this mutation exhibit large amyloid deposits in internal organs, leading to progressive gastrointestinal symptoms and autonomic neuropathy. The international team, including researcher at the CNRS, the École normale supérieure de Lyon, the University College of London, the University of Cambridge and the European Synchrotron Radiation Facility in Grenoble, focused on the characterization of the biochemical differences between the toxic and healthy protein. By means of X-ray crystallography, nuclear magnetic resonance spectroscopy and computational modelling it was possible to understand how the mutation leads to a less stable and far more flexible protein. This flexibility is the key to explain how the protein loses its structure and causes the formation of the toxic fibril.
Le Marchand, T., et al. (2018). Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity. Nature Communications, 9(1), 1658. http://doi.org/10.1038/s41467-018-04078-y