Malignant melanoma is one of the most dangerous forms of cancer. Around half of melanomas and about seven percent of all other cancers carry a mutation in a protein called BRAF. This mutation disrupts the regulation of cell division, causing cells to multiply in an uncontrolled manner. Researchers at PSI and the University of Zurich have now examined the BRAF protein in greater detail, thereby gaining valuable insights into its complex regulation. Among them is Prof. Jörg Standfuss from the PSI, co-author of the publication and head of the research project – supported by the Swiss Cancer Research Foundation – which is investigating the structure and dynamics of B-Raf and its interaction with MEK.
“Cancerous tumours affected by BRAF mutations are considered particularly aggressive and difficult to treat,” says Yasushi Kondo, a researcher at the PSI Center for Life Sciences and lead author of the new publication. There are currently very few active substances available for the targeted treatment of these tumours – and, what’s more, the cells typically develop resistance to these drugs after a few months.
A traffic light that’s always green
Proteins change shape and bind to other proteins and molecules to trigger signalling cascades. The BRAF protein is part of a key signalling pathway in all human cells that functions like a series of traffic lights and regulates cell growth and division. On receiving the appropriate upstream signal, two BRAF proteins bind together to form what is known as an active dimer, giving a green light to the next switch. Without the earlier signals however, the traffic comes to a halt.
Mutated BRAF breaks this control. Instead of waiting for instructions, it turns the traffic light green and remains in this state – irrespective of the rest of the traffic network. This sends the cells a constant signal to proliferate, driving uncontrolled tumour growth.
Scientists already knew that a specific short section of the BRAF protein, known as the NtA sequence motif, plays a crucial role in this cancer-promoting process. Now, Kondo’s team of researchers has succeeded in establishing the role of the NtA motif in greater detail.
They did this by investigating the molecular structure of BRAF dimers at the Swiss Light Source SLS at PSI and at the Diamond Light Source in Didcot, England, and carried out experiments in human cells at the University of Zurich.
The researchers discovered a previously unknown form of BRAF dimer that forms during the signalling cascade. This consists of two BRAF proteins of different shapes, whereby the NtA sequence of one BRAF extends towards its partner in such a way that it forms a kind of bridge connecting the two.