Associate Professor Magnus Kjærgaard, Department of Molecular Biology and Genetics & iNANO, Aarhus University

Intrinsically disordered proteins as regulators of biochemistry
For decades, a key dogma of molecular biology has been that a protein’s structure defines its function. Nevertheless, about a third of eukaryotic proteins have large unstructured regions, and about a tenth are entirely unstructured. These proteins are called intrinsically disordered proteins and are in many ways like organic polymers - albeit with a precisely defined sequence of monomers. Intrinsically disordered regions often regulate folded proteins by tuning their localisation and interactions. For example, many enzymes are tethered to their substrates via disordered linkers, thereby increasing their effective concentration.

We show that interactions linked by flexible linkers follow scaling laws inspired by polymer physics, and that such models can be used to describe how rates of tethered enzymes depend on the architecture of the tether. Tethering is usually reversible and have a defined interaction strength. We show that the highest enzyme activity occurs when the tethering interaction has a moderate affinity and develop a quantitative framework for predicting the optimal tethering strength for a given enzyme:substrate pair. This work thus describes the design principles for reversible enzyme tethers and pave the way for using enzyme tethering in biotechnology.