A study reveals a hitherto unknown protein affinity

For many years it was thought that proteins had to fold into structured scaffolds in order to have any meaningful function. This view has been upended in the last decade, as it has become clear that there are many important regions of proteins that have no permanent structure. These proteins are commonly called intrinsically disordered proteins, or IDPs.

IDPs remain largely unstructured under native conditions, resembling random-coil polymers akin to the unfolded states of proteins. Phosphorylation plays a key role in many signal transduction processes, and preferentially targets intrinsically disordered protein domains. Present in more than 50% of eukaryotic proteins, IDPs perform a plethora of biological functions and are commonly associated with a variety of human diseases, particularly cancer. Cells have many ways to modify IDPs and their interactions, but the specific mechanisms are not yet fully understood. In work coordinated by Gianni De Fabritiis researcher ICREA at CEXS Department and head of the group of Computational Biophysics at GRIB (IMIM - UPF), published in Nature Communications on October 28th; "we show that a modification to a disordered protein known as the Kinase Inducible Domain (KID) not only modulates what shapes it takes, but importantly the time it takes for the changes to happen", said De Fabritiis.

Phosphorylation modulates how proteins interact

While phosphorylation was known to slightly change the conformation of the protein, the kinetic effect was not known. We show that phosphorylation locks the protein in a state that allows for stronger binding to another protein, and that simply increasing the time the protein is locked in that intermediate state can increase binding affinity. This is the first time such an effect has been hypnotized, and could be important for many other interactions between proteins.

This discovery is interesting both fundamentally and practically. From a practical standpoint, having a more complete understanding of such processes could help lead to better therapeutic strategies. Knowing how a mutation changes a natural interaction could lead to ways correct them. While the drugging of IDPs is still largely uncharted territory, it's possible that with lessons learned from our work and others a framework and methods can be built to tackle the challenge.

Reference: Stanley N, Esteban-Martín S, De Fabritiis G. Kinetic modulation of a disordered protein domain by phosphorylation. Nature Communication, 28th October 2014.

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