28 May 2014

Ruedi Aebersold – Unravelling the structure and dynamics of large protein complexes

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New insights into how large protein complexes function differently in healthy and sick cells has now been granted thanks to new technologies.

More than ten years ago, scientists completely mapped the human genome. Now, the attention has turned to enumerating the entire human protein set. Proteins are of interest because they carry out most chemical activities in a cell. But merely knowing the number of proteins within cells is not sufficient to understand how proteins fulfil their biological functions. Ruedi Aebersold, professor of systems biology at the Institute of Molecular Systems Biology at the ETH Zürich, in Switzerland, is one of the pioneers in the field of proteomics. He is known for developing a series of methods that have found wide application in analytical protein chemistry and proteomics. He talks to youris.com about why it is important to analyse the changing arrangement of large protein complexes within cells and how this knowledge may lead to medical applications. Part of his work relates to his role as a partner in the EU-funded project PROSPECTS, completed in 2013, which aimed to gain further insights into the structure and dynamics of protein complexes using novel technologies.

What kind of recent advances have there been in protein characterisations?
The project has advanced the field of large-scale characterisation of proteins in cells. This is through advanced technology and industrial partnerships. The equipment to actually measure out the proteins was significantly advanced. These new techniques were used to characterise the proteome of cell lines and, to some extent, also of tissues. Then the project took some pioneering steps towards characterising the structure of protein complexes. This was in terms of their composition and their orientation in time and space. This is an immensely complicated and challenging question. A lot of progress has been made. But no one in the project consortium will claim that an endpoint has been reached.

Why did you focus on the structure of protein complexes?
It was known very early on in biochemistry that a so-called polypeptide sequence—which make up the basis of proteins—alone does not tell you a lot. A protein complex carries out its function only if it assumes a defined three-dimensional structure. Depending on this structure, the protein will be active or not active. Especially large protein complexes that carry out complex biological functions yet are refractory to traditional techniques. We attempted to learn something about these molecules: Do these structures also occur in a living cell? How do they change if, for example, the living cell divides?

How does this research translate into applications?
For example, there are hundreds of differences between the healthy and the cancer tissue genome in the same individual. So, one important application of these structural-oriented techniques would be to determine how specific mutations that occur in cancer or other disease-associated genes would translate into an altered or defective structure of a corresponding protein complex. Virtually all targets for drugs that are being used in clinical trials are actually protein complexes. So, one would determine how those protein structures, which are causally involved in a particular disease, are different from those in a normal cell. This structural difference would present itself as a target for pharmacological interference.

Could you give a concrete example for pharmacological applications?
Concrete cases are so-called protein kinase complexes. These are more strongly activated in certain cancer cells either through a mutation or because the protein is otherwise altered and interacts with different partners. One would search for preferably small molecules that can revert this activated state into an inactivated one. And thus revert the causal route for this particular disease.

There are large efforts on going in many companies that try to target protein complexes that are involved in particular diseases with new drugs. For example, a compound, called Glivec, inhibits a particular protein kinase. It has been on the market for a while to treat cancer.

What are the main challenges for future research?
One next step would be to make the technologies more robust, more sensitive and have higher throughput. This is because in a cell, hundreds of thousands of such complexes exist. To characterise them in their entirety is still an unreached goal. The most challenging and ultimately most important direction of research will be to determine how these molecular machines function in the context of the living cell. It is one thing to rip the complex out of the cell and to determine its structure and function. It is a whole other challenge and whole other level of complexity to see how this particular machine operates in the cell. How is it regulated? What other structures does it interact with? How does it integrate into the physiology of the cells? I think this is a large frontier for biochemistry and also for clinical research. It will occupy scientists for quite a long time. 

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