The fifth sense of a protein: Quinary interactions in SOD1

The interior of living cells is an eXtremely crowded environment, with a large part of the volume being occupied by diverse macromolecules. For a protein it is like to move in a suburban train at rush hour! However, how this crowding affects the life of a protein, in particular its stability, is still unknown. The group of our collaborator (S. Ebbinghaus at the TU in Braunschweig, Germany) using rapid laser-induced temperature jumps, showed that weak transient interactions with the surrounding macromolecules, often referred to as quinary interactions (aka the fifth order of structural organization of a protein), can indeed amplify and even reverse the stability response of proteins to single-point mutations. By performing innovative multi-scale molecular simulations we shed light on the microscopic origin of those interactions, providing a possible explanation of the experimentally observed stability effects. Together, the results highlight the importance of considering weak transient interactions with the intracellular environment when investigating the relationship between stability and function in vivo as well as possible pathogenic misfolding and aggregation paths. The work is published in JACS, see here.

In vivo stability! Cell type matters.....

In a very recent PNAS, J. Danielsson et al. [see here] present a very interesting work focusing on protein stability in cell. They used in-cell NMR to reconstruct the stability curve of the protein SOD1. The interesting finding is that when the protein is moved in two different types of cells, a bacterial (E. coli)  and a mammalian cell (A2780) the protein is destabilised in both cases. Firstly, this finding questions the common believe that under crowding a protein gets stabilised because of an excluded volume effect. In short, if the available space is reduced because of the presence of a large numbers of macromolecules acting as crowders, the highly entropic and extended unfolded state should be unfavored. This picture is however very simplified since in both folded and unfolded states, a targeted protein interacts with its neighbours, and the results of these specific interactions, i.e. electrostatic, could alter the equilibrium favouring unfolding. The effect of different specific interactions, is actually probed by the authors, showing that by changing the local environment, moving from E.coli to a mammalian cell, the destabilisation effect is different. Last, but not least, the destabilisation results as an increase of the specific heat of unfolding that shrinks the stability curve. This calls for a particular effect of the crowders on the nature of the unfolded state. Stay tune, because the life of proteins in cell is where our interest is going....  

Molecular view of molecular crowding. Project at the Riken HPC center, Japan [see here]