New BRAF protein conformation opens avenues for cancer treatment

Several types of cancer are triggered by mutations in a protein called BRAF. Researchers at the Paul Scherrer Institute PSI have resolved a previously unknown conformation adopted by this protein during cell proliferation. Their study, which has now been published in the journal Molecular Cell, opens new avenues for cancer treatment.

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.

Cancerous tumors affected by BRAF mutations are considered particularly aggressive and difficult to treat."

Yasushi Kondo, 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 tumors - 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 signaling cascades. The BRAF protein is part of a key signaling 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 tumor 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 signaling 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.

An intricate structure

The researchers did not examine this asymmetric BRAF dimer in isolation, but rather in its intricate linkage with another protein called MEK1. "This interaction with MEK1 is a crucial step in the signaling cascade leading to cell division," explains Kondo. This is because the MEK1 protein subsequently moves on, thereby giving the next green light in the signaling chain.

"In this study, we succeeded for the first time in producing a high-resolution visualisation of the exact structure of this complex in its active, working form, which consists of the two BRAF proteins linked asymmetrically via NtA and the MEK1 protein," says Kondo.

This is helpful for drug development: targeted therapeutic agents work by binding to the active components of a signaling pathway, thereby interrupting signal transmission. This sets one of the 'traffic lights' to red and prevents further cell division in the tumor. "The more precisely we know the structure of these components, the more precisely we can design drugs that fit perfectly."

More options for cancer treatment

The researchers hope that a wider range of more effective therapeutic agents targeting BRAF will become available in the future. "This would give us more options when resistance sets in," says Kondo.

In fact, the researchers at the PSI Center for Life Sciences are already searching for molecules that bind to the newly characterised BRAF-MEK1 complex and could thus interrupt the unwanted signaling. "Our findings open up new possibilities for developing drugs that target BRAF in new, different ways," explains Kondo. "Having a broader range of compounds could provide more options for treatment and help address the diverse ways in which cancers evade existing therapies."

The current study was supported by the Swiss Cancer Research Foundation.