Researchers at the Paul Scherrer Institute have identified a previously unknown conformation of the BRAF protein, which is implicated in several types of cancer, according to a July 21 announcement. The study, published in Molecular Cell, reveals insights into how this protein behaves during cell proliferation and may inform future cancer treatments.
Malignant melanoma remains one of the most dangerous cancers. Approximately half of melanomas and about seven percent of all other cancers carry mutations in the BRAF protein. These mutations disrupt normal regulation of cell division, causing uncontrolled cellular growth. Scientists from the Paul Scherrer Institute and the University of Zurich examined BRAF's molecular structure to better understand its complex regulatory mechanisms.
Currently, there are limited targeted therapies for tumors driven by mutated BRAF, and resistance to available drugs often develops within months. Proteins such as BRAF change shape and interact with other molecules to trigger signaling cascades that regulate cell growth. Normally, two BRAF proteins form an active dimer only after receiving specific signals—this acts like a traffic light system for cellular processes. However, mutated BRAF can bypass these controls and continuously signal cells to divide.
The research team focused on a short section called the NtA sequence motif within BRAF that plays a key role in this process. Using facilities at Swiss Light Source and Diamond Light Source in England, along with experiments at the University of Zurich, they discovered an asymmetric dimer form where one NtA sequence bridges two differently shaped BRAF proteins during signaling events.
Kondo's team further analyzed how this dimer interacts with another protein called MEK1: "This interaction with MEK1 is a crucial step in the signaling cascade leading to cell division," explains Kondo. The study produced high-resolution visualizations showing two asymmetrically linked BRAFs connected via NtA alongside MEK1: "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..."
These findings could assist drug development by enabling more precise targeting: "The more precisely we know the structure of these components, the more precisely we can design drugs that fit perfectly." Researchers hope their work will lead to new therapeutic agents capable of overcoming drug resistance: "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.
