Kiss and run: cells work optimally when molecules connect transiently

Breaking new ground 3. jul 2022 3 min Associate Professor Magnus Kjærgaard Written by Morten Busch

Stigma may be attached to people who have many partners and one-night stands, but this is the basis of optimal functioning inside cells. New research shows that the contact between the key parts of the body’s machinery – enzymes – must be transient to optimise the processes. However, the new knowledge is far from just an interesting curiosity. It will help to create new and better drugs that can regulate cellular errors and design industrial processes in which enzymes contribute to more sustainable production.

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Cooked spaghetti, Goldilocks and promiscuity are not normally associated with descriptions of how physiological processes are regulated. However, the molecular mechanisms of cells have often challenged the classical view of a finely tuned assembly line, and researchers have had to use creative language to understand and explain these mechanisms. A new remarkable research breakthrough adds yet another example.

“When two molecules connect inside our cells, the duration of their interaction is crucial. Their interaction must be neither too strong nor too weak. It should ideally be “kiss and run”– a rapid intense meeting and then on to the next connection. This new knowledge can help us to understand how small changes in genes can strongly affect signalling pathways but may also be used to optimise pharmaceutical drugs and the enzymes used in the biotechnology industry,” explains Magnus Kjærgaard, Associate Professor, Department of Molecular Biology and Genetics, Aarhus University.

In the Goldilocks zone

Enzymes are omnipresent in our everyday lives – such as in laundry detergent for removing stains and mashing in beer brewing – but their most important functions are in human cells, where they drive almost all processes. At least 4,000 enzymes keep our body tuned, and most are very specialised and select a specific substrate, which they can break down or modify. The new research examines the mechanism by which an important type of signalling enzymes, kinases, recognise their substrates.

“The general equations we have developed to predict the optimal binding strength between enzymes and their substrates conclude that it should preferably be of intermediate strength: neither too strong nor long-lasting but also not too weak and short-lived. This is the first time that this intermediate strength has been quantified, and this provides a tool to understand enzymes in signalling pathways in cells and especially what happens when they are affected by mutations in certain diseases,” says Magnus Kjærgaard.

Until recently, a dogma of biology was that proteins had to have a well-defined structure to communicate with each other. In the past decade, however, many proteins have been discovered to function without having a fixed shape, thus changing our view of how the molecules of life work. Instead of thinking of them as folded into solid structures, many proteins today are considered more disordered and dynamic – like cooked, dancing spaghetti.

“This instantly revolutionised our understanding of how proteins function and is the basis for our new study of kinases. We wanted to understand how the binding strength – affinity – of the spaghetti region to the substrate affects enzymatic activity and how to potentially create a new artificial interaction that is optimal. It is like Goldilocks and the Three Bears – the porridge must be neither too hot nor too cold. Similarly, we want to be in the Goldilocks zone, where the interaction is neither too strong nor too weak – but just right,” explains Magnus Kjærgaard.

Molecular glue

Traditionally, enzymes and their substrates have been considered a lock with a key. When the wrong key is used, the enzyme remains inactive. When the right one is used, it catalyses a specific process in the cell. The discovery of unstructured proteins has added a layer to our understanding of how enzymes recognise their substrates. The enzymes use spaghetti-like tails to find the right home.

“The domain in which the molecule has the first contact with the enzyme – the docking interaction – is often structurally independent of the domain in which the chemical or molecular reaction itself takes place. This enables considerable flexibility and many combination options in designing new and better enzymes to replace chemical processes in industry. We can use our new tools to calculate which docking modules are optimal and thus design more efficient processes,” says Magnus Kjærgaard.

The researchers’ equations can thus be used to understand the effect of specific mutations that cause small changes in individual amino acids in the key parts of the enzyme or to design whole modules to optimise the contact between the molecules. However, the new knowledge is expected to have applications in more than just the biotechnology industry and may also be especially useful for designing new drugs.

“There is potential in being able to use drugs to target specific proteins that play a key role in such diseases as cancer. However, attacking these proteins with the usual small molecules has proved to be difficult because of their special structure or lack thereof. Instead, a type of molecular glue called proteolysis-targeting chimeras (PROTACs) can be used to target and degrade the proteins. We think our new calculation model can work wonders based on the specific design of the PROTACs, and now that we have established the theoretical basis, we look forward to testing this in the laboratory,” concludes Magnus Kjærgaard.

The optimal docking strength for reversibly tethered kinases” has been published in the Proceedings of the National Academy of Sciences of the United States of America. The project has received grants from the Velux Foundations’ Villum Young Investigator Programme, the Danish National Research Foundation and the Novo Nordisk Foundation through the project BOUNDLESS Signalling in Membrane-less Organelles: A New Phase in Cellular Biology.

Our research group studies dynamic and disordered proteins using biophysical and biochemical methods. We are especially interested in intrinsically di...

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