Understanding MYC’s Structure and Function

In a study published today in Nature Structural and Molecular Biology, scientists identified how the MYC protein, which plays a central role in cancer, binds to TATA-binding protein (TBP) and controls important functions in the cell. The new discovery may inform development of new cancer drugs that could disrupt the function of MYC in tumor cells.

The MYC protein regulates many important functions in healthy cells, but it is often extremely overactive in aggressive tumors. Nonetheless, the mechanisms by which MYC functions in the cell have been largely unknown. Thus the current study investigated how the transcription factor MYC interacts with TBP, which acts as a “start button” for the expression of many genes in the cell.

MYC, however, has proved to be elusive for structural biologists. It is what is known as a “disordered protein” because it constantly shifts between different structures. Around 70% of proteins implicated in cancer development are disordered proteins, so understanding their function could help inform development of new cancer treatments. In the study, the researchers captured an instantaneous image of MYC bound to TBP and have studied the protein complex using methods such as crystallography, NMR, and mass spectrometry.

“We already suspected that there was a binding site on the seat of the saddle-shaped TBP protein,” says senior author Maria Sunnerhagen of Linköping University. “But the first thing we found by crystallography was how MYC binds the concave side of the TBP ‘saddle,’ which we weren’t expecting.”

Next, the scientists created mutations of MYC that removed different features of the binding site and investigated how it affected protein function and cell growth. “We have shown that both binding sites influence MYC activity and affect cell growth and proliferation,” Sunnerhagen says. “Breaking the interaction between MYC and TBP dramatically decreases the ability of the cells to survive.”

The scientists have not yet been able to directly image the dynamic binding site that has the greater biological function at atomic resolution. Instead, they combined data from different methods and used a supercomputer to model the interaction between the two proteins. They then used AI to home in on the structure that agrees best with the observed data and identified a previously unknown binding site. Based on their findings, the researchers believe that MYC helps to increase gene expression by making it easier to place TBP at the correct location on the DNA.