Structure of Cancer-Related Protein Revealed

Unregulated cell division is a hallmark of cancer. Cell division is controlled by many proteins, among them a transcription factor called FoxM1. Abnormal activation of FoxM1 is common in cancer cells and is correlated with poor prognosis, metastasis, and resistance to chemotherapy.

In a study published today in eLIFE, researchers at UC Santa Cruz used NMR spectroscopy to determine the structure of FoxM1 in its inactive conformation. This new understanding could ultimately be used to design new drugs that stabilize the protein in its inactive state and could thereby stop the uncontrolled proliferation of cancer cells.

“When a cell is going to divide, there are a bunch of proteins that need to be made, and FoxM1 controls all the genes for those proteins,” says senior author Seth Rubin. “Because cancer cells are proliferating and dividing all the time, they need to activate FoxM1, so it has long been a target for drug development.”

After determining the structure of FoxM1 in the ‘off’ state, the team looked into how it switches to the ‘on’ state. The study revealed that two separate domains of the FoxM1 protein interact and bind together in the inhibited conformation. These two domains separate and lose their structure when the protein is activated.

“One thing a disordered state is good at is interacting with other proteins,” Rubin explains. “With FoxM1, the inactive state is all folded up on itself. When it gets activated it becomes disordered, and then it can recruit the other proteins needed to turn on gene expression. That’s something that hasn’t been seen before, and it may be a general mechanism for how transcription factors switch from the ‘off’ state to the active state.”

Previous studies have shown that FoxM1 is activated by kinase enzymes, which add phosphoryl groups to specific sites on the protein. Rubin’s team found that phosphorylation of FoxM1 at one particular site causes the dissociation of the two domains and that both domains then become structurally disordered.

“Knowing the structure of the inhibited state of the protein really opens up a pathway to search for compounds that can stabilize it,” Rubin says. “And beyond drug development, in terms of the understanding of how transcription factors work, the discovery of this transition from an ordered to a disordered state is an important advance.”