Convincing scientists to collaborate with a man who promotes disorder may seem like an odd goal at first, but it’s exactly what Peter Tompa is doing at VIB. Tompa is one of the scientists who founded the field of intrinsically disordered proteins, overturning the dogma that proteins need a fixed three-dimensional structure to function. Instead, say these scientists, many proteins actually require disorder to complete their tasks. As of May, Tompa will take over from Lode Wyns as Director of the VIB Department of Structural Biology Brussels, Vrije Universiteit Brussel. “The breakthrough is taking place right now. I invite all VIB departments to take part in this revolution.”
When did you realize that disorder, instead of structure, was important for some proteins?
Peter: For a long time I had been working on two proteins that did not fit the ordinary pattern – an inhibitor of an enzyme and a cytoskeletal protein. It was impossible to determine the position of their atoms with traditional techniques such as X-ray diffraction. This disorder violated the rules, but it didn’t occur to me at the time that it was important to study. And then, all of a sudden, during a three-month stay at Tokyo University in 2000, I realized that the difference did matter and that I wanted to understand the relation between disorder and function.
How did this field develop?
Already before 2000, Peter Wright and Keith Dunker had published some papers about proteins without a rigid structure. As other people joined the field, myself included, it became clear that disorder was in fact widespread. However, a lot of scientists didn’t like the idea and there was widespread skepticism. But starting around 2005, because of our activities in bioinformatics and our experimental studies, the idea that disorder plays a role in many systems started to gain acceptance. Today, it is assumed that around 50% of all human proteins contain at least one intrinsically disordered segment.
Are there two classes of proteins: structured versus disordered?
No, that’s not the case. Many proteins have both folded units and disordered segments – all of them contributing to the function of the protein. Besides, there is a continuum between rigidly folded states and completely disordered ones. We have now a fundamentally new picture of how protein sequence, structure and function are related. In a functional sense, structure and disorder are about the same thing: the spatial conformation – conformational ensemble – of proteins is key to the whole of life.
"I see a lot of opportunities for collaboration, whether people are working on disordered or ordered proteins." - Peter Tompa
What biological questions will you focus on in your own VIB research group?
I want to address this newly discovered complexity of proteins. In one project, I would like to create an artificial intrinsically disordered protein, to show that we have a deep understanding of the underlying principles of disorder. These days, protein design is focused on creating enzymes with new specificity, or working under harsh conditions. But because we do not understand the secrets of enzymes in every detail, the new enzymes usually perform several orders of magnitude worse than the ones found in nature. My bet is that we understand intrinsically disordered proteins (IDPs) so well by now that we can create one that is as good as any evolved IDP. We’ll beat the guys designing enzymes, because IDPs are much more tolerant to mutations. We will be much freer to play around with elements.
Another project I want to set up is looking at how IDPs behave inside a living cell. IDPs do not have a single, stable structure. They continuously morph into various shapes, probably due to the presence of other molecules. We want to look at the effect of crowding on IDPs. How does a disordered protein react to a community of thousands of other proteins packed together? We are going to combine in-cell functional studies and structural studies by in-cell NMR to find it out.
The third project is about the importance of disorder in large proteins, composed of several domains and disordered linker regions. I plan to focus on CREB-binding protein, create nanobodies against all its domains and solve the spatial relationship of all its domains and other binding elements in its structure. This will be done in collaboration with Peter Wright from Scripps in San Diego, and we will use mass spec, EM and atomic force microscopy, among other techniques.
What made you decide to come to VIB?
I joined VIB for its high-level scientific infrastructure – the equipment, instruments, people… I find the scientific atmosphere here very stimulating. From what I’ve seen and heard so far, VIB is brimming with scientific energy. It’s a great place for doing good science, for taking my research to a higher level.
"I am planning to visit all the departments and explore possible joint research projects." - Peter Tompa
What are your plans for the Brussels department?
I want this department to be clearly focused on structural biology, to become a top structural biology centre. Therefore, we need the complete toolkit of protein research. Some key technologies are already in-house, including NMR, EM and X-rays. Others might be arriving soon: SAXS (small-angle X-ray scattering) and a cryo-electron microscope, for example. And most importantly, there are a lot of excellent scientists here, working on diverse topics. They are very knowledgeable and dedicated to their research. Their focus should be on solving biological problems, with structural biology as a tool.
How do you see the interaction with the other VIB departments?
I see a lot of opportunities for collaboration, whether people are working on disordered or ordered proteins. Wherever I go, around 50% of the groups immediately become interested in disordered proteins and see connections with their own work. But these collaborations will be much more than just solving and depositing the structure of a protein. They should raise the research to a higher level. We want to understand the biological function of the structures. We want to look at what lies beyond the mere coordinates of atoms. I am planning to visit all the departments and explore possible joint research projects.