Wageningen University & Research: International team delves into the hidden life of disordered proteins

Almost everything we know about proteins is derived from research into folded proteins. Yet about half of proteins are unfolded, or rather, disordered. Thanks to a special grant, Professor of Biochemistry Dolf Weijers and his colleagues overseas will be able to spend the coming years conducting research into this type of protein.

Proteins are microscopic molecules that perform several important functions within and between the cells in our bodies, from transport and communication to the generation of energy. Anyone who has ever browsed through a biology book will know that these proteins are made up of chains of intricately folded amino acids. The function of a protein is determined by this ingenious folding process.

Important role unstructured proteins
However, not all proteins are so beautifully folded; about half also have long, unstable sections that are as randomly formed like a string of spaghetti in a pot. Dolf Weijers was recently awarded a research grant by the Human Frontier Science Program to study these disordered proteins in more depth. “Our whole thinking about proteins is based on neatly folded chains, and how this structure determines the function of a protein. In recent years, it has become clear that unstructured proteins also play an important role, and this is turning everything on its head. That is what makes this field of research so exciting.”

Weijers particularly wants to know which properties of these disordered proteins determine the function of the protein. The function of a ‘normal’ protein is locked into its fixed, three-dimensional folded structure, which determines whether the protein is responsible for transport, communication or another task. But since unstructured proteins do not have a fixed shape, we can only guess how such a protein knows what role to play.

Modify disordered proteins
Weijers and his colleagues Alex Holehouse (Washington University) and Hyun Kate Lee (University of Toronto) think that evolutionary insight could provide the answer. By applying clever techniques to calculate back in time, you can work out which chains of amino acids in disordered proteins have remained the same over millions of years. The researchers deduce that the function of the protein must be built into these specific chains. For this research, Weijers will modify a disordered protein of the plant liverwort. This will allow the researchers to study how the properties of an unfolded protein determine its function.

We are really working on the frontiers of knowledge here
Dolf Weijers
“This is truly exiting and ground-breaking research, and it is far from certain that we will achieve our objective, which is why it’s wonderful that we have received this grant from the Human Frontier Science Programme,” says Weijers. “Many science funders want a guarantee that something concrete will come out of the research, but that is simply too hard to predict with fundamental research of this kind. We are really working on the frontiers of knowledge here.” With the grant of approximately €1 million, the researchers in Wageningen, Washington and Toronto can get to work to unravel this mystery.