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White specks on the map of life

Text: Katrin Bühler

How are signals processed and building blocks produced inside cells? How do diseases develop? Resolving structures of complex proteins enabled researchers at the Biozentrum to answer such questions.

3D model of the protein complex mTORC1. (Image: University of Basel, Biozentrum)
3D-model of the human mTOR complex I. (Image: University of Basel, Biozentrum)

Every day, his coworkers in the laboratory grow thousands of crystals – but not the kind you would usually find at mineral shows or as items of jewelry. The researchers crystalize proteins to decipher their structure and function using X-ray crystallography. For Professor Timm Maier, these are the most beautiful crystals in the world: “They may be tiny, but protein crystals are more appealing to me than any diamond. And they are not just beautiful on the outside; they also shed light on the molecular dimensions of life.” A structural biologist,

Maier has been conducting research at the Biozentrum since 2011 and specializes in the giants among these tiny structures – large protein assemblies. “I am fascinated by their complexity and diversity,” he says. “This is by no means restricted to their structure. We are constantly amazed by their dynamics, their multifaceted functions, and the ways in which they can be regulated. These tiny protein structures are as complex as entire factories.”

Protein factory for fatty acids

Fatty acid synthase is one such miniature factory. This enzyme produces fatty acids, which are components of cell membranes and serve as important energy stores. When Maier began to study this enzyme over ten years ago, its structure was completely unknown. Some renowned scientists even believed that it would never be possible to clarify its structure. Maier took on the challenge – with success. “Getting to the bottom of a previously wholly unknown structure is thrilling,” he states. “You see things that nobody has ever seen before, and suddenly you can understand truly fundamental processes. You feel like Columbus must have done when he first set foot on uncharted terrain.”

Thanks to Maier’s X-ray crystal structural analyses, we now know – in detail – how fatty acid synthase is structured: It is made up of 14 protein regions that create one long, water-insoluble fatty acid chain from small molecule components in a sequence of over 40 reactions. “Now, years after initially clarifying the structure, we are just beginning to understand the interplay of dynamics and catalysis in fatty acid synthase.”

Starting points for new medications

Fatty acid synthase does, however, have a dark side too: Increased activity in this protein factory contributes to rapid tumor growth and the proliferation of cancer cells, making it an interesting target for cancer therapy. Using the structure as a basis, researchers worldwide can now investigate the binding and effects of new inhibitors.

The protein TOR plays an important role in regulating fatty acid synthase and numerous other enzymes. Together with further proteins, it forms the large TOR complex I – the control center for cell growth. Together with other scientists, Maier has succeeded in clarifying the architecture of this huge complex. “TOR inhibitors are already being used in cancer therapy, and there is great potential for further development. The protein complex has long been one of the most important goals in structural biology,” says Maier. “Figuring out the architecture of the TOR complex was a major challenge that could only be tackled with intensive collaboration and by combining several techniques. And this is not an isolated case. We increasingly find ourselves tackling questions that can no longer be answered using just one method. We are therefore glad to receive strong support from the Biozentrum for interdisciplinary projects.”

In a recent Nature publication, Maier’s research group investigated the architecture of polyketide synthases. These enzymes occur in bacteria and fungi and serve as molecular factories for naturally occurring bioactive substances. They are natural producers of antibiotics and the TOR inhibitor Rapamycin, which gave the TOR protein its name (target of rapamycin). “We have established that polyketide synthases have an extremely variable and flexible structure,” says Maier. “During the process of evolution, their versatile structure tolerated variations of entire protein segments and, therefore, enabled the development of a wide variety of products.” This feature also makes polyketide synthases interesting for the development of drugs – with the aid of newly formed protein variants, a wide range of medication precursors could be produced that are difficult to chemically synthesize.

Detailed picture

Structural biology has changed considerably over the last few years – it has become integrative. Having previously tackled isolated questions with individual technologies, now researchers combine a wide variety of methods. Technologies range from X-ray crystallography, to electron microscopy, through to nuclear magnetic resonance and mass spectroscopy. Thanks to enormous technical progress and the variety of methods available, researchers can now – quite literally – obtain a much more detailed picture of extremely complex proteins.

“From the start, I was fascinated by the prospect of visually exploring the structures of life. We obtain three-dimensional images of proteins, examine them from all angles, and then decipher their architecture,” states Maier. “At the same time, we get fundamental insights into the workings of cells in which proteins process signals, synthesize substances, and transport molecules. Protein structures are one of the keys to understanding life,” says Maier with a twinkle in his eye.

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