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The body can get rid of cells that are unnecessary, infected or damaged by instructing them to go through a process known as apoptosis, which results in the cell killing itself. These orders are given in the form of pro-death molecules, such as the BH3 proteins, which kick start apoptosis.
In order to survive and multiply, cancer cells can increase the levels of anti-death proteins which bind and ‘trap’ BH3 proteins, preventing them from triggering apoptosis. At the molecular level, the process involves the anti-death proteins recognizing and attaching to a specific ‘BH3 sequence’ in the pro-death signals.
A new type of anti-cancer treatment works by tricking the anti-death proteins into binding a drug rather than BH3 proteins, which are then free to induce apoptosis. These decoy drugs mimic the BH3 sequences that the anti-death proteins recognize and attach to. However, studies have shown that the BH3-protein Bim stays bound to the body’s anti-death proteins rather than being displaced by the drugs. In patients, this means that the cancer cells may resist and survive the treatment.
Here, Liu et al. try to understand why Bim keeps on attaching to anti-death proteins by developing an advanced microscopy technique to dissect the interactions between the two types of molecules. This revealed that Bim has a second sequence for binding to anti-death proteins, which is located far away from the ‘normal’ BH3 sequence. Together, the two sequences allow Bim to double-bolt lock to anti-death proteins, which explains why it cannot be displaced by drugs that mimic only the BH3 sequence.
In the future, the new binding sequence may serve as a target for anti-cancer drugs. The microscopy technique developed by Liu et al. can also be used to study other pairs of interacting proteins.
