Scientists at the University of California, Santa Cruz, say they have determined the structure of transcription factor FoxM1, a master switch for cell division, in its inactive or off conformation. This new understanding of the protein’s structure could ultimately be used to design new drugs that stabilize the protein in its inactive state and thereby stop the uncontrolled proliferation of cancer cells, according to the researchers.

“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,” said Seth Rubin, PhD, professor of chemistry and biochemistry. “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.”

The new study (“An order-to-disorder structural switch activates the FoxM1 transcription factor”), which appears in eLife, involved a close collaboration between Rubin’s lab and that of Nikolaos Sgourakis, PhD, assistant professor of chemistry and biochemistry. After determining the structure of the protein in the “off” state, the team then figured out how it switches from the inhibited conformation to the activated or “on” state.

“Intrinsically disordered transcription factor transactivation domains (TADs) function through structural plasticity, adopting ordered conformations when bound to transcriptional co-regulators. Many transcription factors contain a negative regulatory domain (NRD) that suppresses recruitment of transcriptional machinery through autoregulation of the TAD,” the investigators wrote.

“We report the solution structure of an autoinhibited NRD-TAD complex within FoxM1, a critical activator of mitotic gene expression. We observe that while both the FoxM1 NRD and TAD are primarily intrinsically disordered domains, they associate and adopt a structured conformation. We identify how Plk1 and Cdk kinases cooperate to phosphorylate FoxM1, which releases the TAD into a disordered conformation that then associates with the TAZ2 or KIX domains of the transcriptional co-activator CBP. Our results support a mechanism of FoxM1 regulation in which the TAD undergoes switching between disordered and different ordered structures.”

The study revealed that two separate domains of the FoxM1 protein interact and bind together in the inhibited conformation. The study also showed that the two domains separate and lose their structure when the protein is activated. Most proteins fold into an orderly three-dimensional structure that is key to their function, but some proteins function as disordered linear molecules with no particular 3D structure.

“One thing a disordered state is good at is interacting with other proteins,” Rubin said. “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.”

It was known from previous studies 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 said. “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.”

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