Proteins are long polymer chains, composed of a sequence amino-acids, directly coded in the genome. The chemical variety of the 20 natural residues allows the proteins to perform nearly all the functions of life. They insure the structure of the organism, the chemical activity (enzymes) and the mechanical movements (motors). They regularly perform exquisitely precise functions, at room temperature and in water, with accuracies, yields, and reproducibilities which are miles ahead of what the best chemists are able to do today. This was recognized since the very beginning of modern chemistry and E.Fischer, as early as 1890, proposed the lock-and-key paradigm to explain these capacities of natural enzymes. This paradigm has known a tremendous success, and the fist protein structures, showing a precise spatial organization of the protein backbone and of the amino-acid side-chains confirmed this description.
However, it was also realized that the formation of the proper fold from the nascent protein chain, produced by the ribosome, is not a simple process and has to be guided in some way (the Levinthal paradox). Additionally, a lot of internal dynamic remains in the folded state, and it usually presents only a small energy advantage over the unfolded states.
In the latest 20 years, with the development of the Creutzfeldt-Jakob and other amyloid-related diseases, it was recognized that the same protein sequence can adopt alternative stable folds. It was further found that nearly all proteins can adopt the amyloid fold, which was then considered as a pathological thermodynamic trap. More recently, is was discovered that some protein chains display an intrinsically disordered state, which eventually acquire a temporary fold, but definitely departing form the lock-and-key pattern. Furthermore, these Intrinsically Disordered Proteins (IDP) were acknowledged to represent nearly 30% of the protein material in eukaryotes.
These discoveries have profoundly changed the way we have to think about protein activity and regulation.
A real cell is not like a test tube, it is an out-of-equilibrium complex medium, where proteins interact with many partners, with diffusion/reaction competition, and spatial compartmentalization.
I will take the example of the Androgen Nuclear receptor protein; a 960 amino-acids protein involved in the action of the testosterone. This protein interacts with androgen hormones, with DNA, with the transcription initiation factor, and with dozens of regulatory proteins. Strikingly, half of the protein sequence is in IDP state. It was found recently that two independent amyloid prone sequences are located in the IDP domain. One of these sequences is able to trigger the amyloid formation by the modification of the redox state of a sulfur atom, resulting in a possible non-pathological regulatory amyloid state. I will show how the change of this single atom can change the behavior of neuron cells in which this molecule in protein is present.