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The Two Steps of a Protein's Life


By combining two NMR techniques, researchers from IBS track certain furtive, yet essential states of a protein's functioning. A first application has already been found in joint and bone pathology.

Published on 27 April 2017
​The life of a protein is all about change. Its conformations evolve constantly depending on the environment. Biologists have long observed them in their state of lowest energy, i.e. their state of equilibrium, which was long thought to be the most frequent and therefore the most significant. "Yet today we know that higher-energy alternative conformations, also called excited states, often play a significant role in the protein's function or its involvement in a disease," said IBS researcher Bernhard Brutscher. Nuclear magnetic resonance (NMR) spectroscopy has become a prime technique for observing the life of proteins.

"NMR spectroscopy makes it possible to study the dynamics of proteins at the atomic scale over a broad time scale," Brutscher said. "We have combined two NMR techniques to access information that was out of reach up to that point." First, the researchers from IBS used real-time NMR to access a transient state of the protein that becomes visible during refolding, for a period of about twenty minutes. A second NMR technique, called relaxation-dispersion NMR, allows to "zoom" on this transient state, in order to observe even more fugitive states (of the order of a millisecond), but potentially important for the role of the protein in a living organism. By combining these two methods, the scientists were able to characterize a transient state in β2-microglobulin, a protein that forms amyloid fibrils in dialysis patients, causing amyloidosis along with joint pain and increased bone fragility. "We detected a dimeric configuration of the protein in exchange for the monomeric configuration in this transient state," says Brutscher. "This dimeric transient state can be considered as causing the onset of this process of aggregation and fiber formation."

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