The mystery of flexible proteins

15 May 2018

Professor Edward Lemke conducts research into intrinsically disordered proteins. Among other things, he has developed new methods of observing these albumins. He has been a professor at the Faculty of Biology of Johannes Gutenberg University Mainz (JGU) since January 1, 2018. Here he works in collaboration with the Faculty of Chemistry, Pharmaceutical Sciences, and Geosciences. He is also Adjunct Director of the Institute of Molecular Biology (IMB) and a Fellow of the Gutenberg Research College (GRC).

"Imagine a pan full of cooked spaghetti," suggests Professor Edward Lemke. "You would never expect that the strands could be put into a sensible shape so that they could perform a task of some sort. But that is precisely the case with intrinsically disordered proteins. Previously it was assumed that proteins needed to be folded in order to function. Today, however, we know that up to 50 percent are not folded. They are flexible molecules – so, not unlike spaghetti." Over the last 20 years, this knowledge has fundamentally altered the view of proteins. Lemke is among the leading researchers constantly making new discoveries in this rapidly expanding field.

The biophysical chemist took up a professorship post at JGU’s Faculty of Biology at the beginning of the year. Lemke has already moved into his office on the Gutenberg campus, but for the time being his team is still in Heidelberg, where he has worked on research programs at the European Molecular Biology Laboratory (EMBL) since 2009. "We did not want to break up the group. With ten members, it is a large team and there is not enough suitable space in Mainz at the moment." That will change in 2020. "The BioCenter II building will then be ready and we will be assigned modern laboratories within it."

Involvement in expansion

This may all seem a somewhat inelegant way of going about things, but there is a very definite reason why the chemist accepted the appointment as Professor of Synthetic Biophysics in Mainz. "This university is investing hugely in the life sciences and the Faculty of Biology is being reorganized. Now’s a good time to become involved in research here. Moreover, the scientific environment is right." Lemke mentions the Institute of Molecular Biology (IMB), where he has been appointed Adjunct Director. And he refers to another aspect: "In Mainz, prominence is also given to polymer research. And polymers are not so far removed from proteins. I can well imagine collaboration in this connection." He was also persuaded by the concept of the Gutenberg Research College (GRC), which has already welcomed him as a Fellow. "It is an excellent strategic tool that enables support to be targeted more effectively to certain fields."

But that’s enough for the present about what he likes about Mainz. Lemke also wants to talk about his research, for which he has gained global recognition. "Proteins are an important building block of all living matter, from which molecular machines can be built to perform a wide range of tasks." It’s all relatively straightforward in the case of folded proteins; they take on a particular form and become part of a machine. "But intrinsically disordered proteins do not have a fixed shape, and are completely flexible. How is it possible to have a specific machine that works on the basis of these spaghetti molecules? That is what interests us."

The material used by Lemke’s team includes somatic cells – or more precisely, their nuclei that are encased in membranes. These membranes each contain several hundred nuclear pores. "They consist of a ring which is formed from folded proteins. We can recognize them clearly under the microscope. But teeming within these rings are intrinsically disordered proteins which no one has really properly perceived before. They filter what can pass into and out of the cell nucleus." The traffic between the cell and its nucleus is enormously active, so the task is huge. "We are looking at several thousand shuttle events per second. Whatever wants to enter or leave needs a key." This key docks on to substances in order to enable their passage. The lock is a conglomerate of spaghetti molecules within each nuclear pore.

Exploring cells using probes

These processes are difficult to observe. Lemke’s group has developed an elaborate technique that makes use of fluorescence: "There are certain pigments that we can induce to glow. We send these into cells and then observe what happens using high-resolution microscopes. It is enough to introduce a single molecule into the system. What is unusual here is that we do not obtain an instantaneous image, or snapshot, as in the case of other methods, but a sort of short film that shows us a process taking place." Of course this is only a small excerpt of what happens, and so molecule after molecule is sent off in order to see more of the various connections. "We do this several thousand times."

It turns out that intrinsically disordered proteins are capable of performing a wide range of tasks. They can even fold, if necessary. Ultimately, they can do more and are more versatile than their permanently folded counterparts.

"But nature took a risk here," explains Lemke. "Spaghetti molecules are more vulnerable if, for example, they are attacked by viruses." Lemke’s team has investigated this aspect in the case of HIV and hepatitis viruses. "The viruses have greater problems altering the function of folded proteins. First they have to be unfolded. That is, of course, unnecessary in the case of spaghetti molecules."

So-called amyloid fibrils play a decisive role in degenerative diseases such as Alzheimer’s and Parkinson’s. "Here the proteins take the form of extended structures and damage the cells. Intrinsically disordered proteins are also more susceptible to this." But their usefulness clearly outweighs these disadvantages.

DFG Priority Program

Lemke undertakes fundamental research. He wants to know precisely how the spaghetti molecules function. For this, he has assembled a cross-disciplinary team in which physicists, chemists, microbiologists and technicians work closely together. "We are just at the beginning," he says. "We still have a lot of work ahead of us."

A Priority Programme recently set up by the German Research Foundation (DFG) focusing on molecular mechanisms of functional phase separation could help to promote a further aspect of this research field. Lemke has been appointed its coordinator. Here too the spaghetti molecules again come into play. They can join together and form drops, and thus create compartments - separate spaces in a cell that perform a very specific function and dissolve again when they are no longer required.

"We have known about these compartments for some time but have only a limited idea of how they function on the molecular level. I’m sure that will soon change.” Across Germany, researchers have the opportunity to put their projects forward for sponsorship through the new DFG Priority Programme strategy. "I can well imagine that some of the groups in Mainz will be involved," says Lemke. "After all, we’re already off to a flying start here.“