About 2,300,000 people are diagnosed with breast cancer every year. Of these, approximately 70,000 have mutations in the breast cancer gene 1 (BRCA1), which encodes the BRCA1 protein.
BRCA1 plays a critical role in DNA damage repair. People with mutations in bRCA1 are less able to repair damage in their DNA, leading to an increased risk of cancer.
Therapeutics that enhance BRCA1 function would be a valuable means to counteract deleterious mutations. However, its unclear how to achieve this goal.
In a recent preprint, Bhattacharjee et al. use simulations on Folding@home to understand how mutations alter BRCA1 function, revealing a previously unknown role for protein dynamics.
One key finding is that BRCA1 rarely adopts structures that are compatible with binding other proteins, like BARD1 and UBcH5c. This finding may be surprising to some since experimental structures of BRCA1 on its own or bound to these other proteins all look basically the same. However, the isolated protein is floppy and actually only rarely adopts the conformations seen in those structures in the absence of binding partners.
A second finding explains why BRCA1 only binds UBcH5c after binding BARD1. Again, this fact is surprising if you think the protein always looks the same. However, once you see how floppy the isolated protein is, it starts to make sense. The binding interface for UBcH5c is particularly floppy, at least until BARD1 binds to and rigidifies BRCA1. Then BRCA1 has a higher probability of adopting structures that are compatible with binding to UBcH5c.
Lastly, these simulations give insight into how mutations implicated in disease and others that help BRCA1 function work. The mutations that cause cancer make BRCA1 even more floppy, preventing BARD1 from enhancing interactions with UBcH5c. In contrast, the mutations that protect against protein dysfunction stabilize the protein, enhancing its ability to interact with its binding partners.
Together, these results suggest that one could counteract deleterious mutations that increase cancer risk by designing small molecules, peptides, or other therapeutics that stabilize BRCA1 and help it to function properly. Research in this direction is now underway!