Biophysical Journal, The Premier Journal of Quantitative Biology, Volume 116, Number 6, March 19, 2019,, Biophysical Society, Cell Press

FREDERICK, Md. -- A study defining how an oncogenic protein gets removed from its active spot may offer new ways to target unwanted cell growth, a hallmark of cancer.

KRAS is a membrane-binding protein that functions as a molecular switch to regulate cellular activity, and is the most frequently mutated oncogene in human cancer. Normal KRAS controls cell growth. When KRAS is mutated, the signal is disrupted and cells grow continuously. 

KRAS is made up of three parts, a main body globular domain, a highly charged C-terminal domain, and a lipid tail which it uses to hang on to the cellular membrane. It’s at the cell membrane where normal KRAS does its regular function while oncongenic KRAS begins to do its damage.

In a study published in Biophysical Journal, Constance Agamasu and others from the Frederick National Laboratory for Cancer Research investigated how a KRAS binding partner called Calmodulin (CaM) removes KRAS from the cellular membrane. CaM is a multifunctional intermediate calcium binding messenger protein expressed in all cell types.

The authors used a combination of investigative techniques including Analytical Ultracentrifugation, Surface Plamson Resonance, and Nuclear Magnetic Resonance to study the interaction between KRAS and CaM. Their studies show that CaM uses its hydrophobic pockets to attach to the lipid tail of KRAS. This keeps the lipid tail from attaching to the cell membrane.

Since CaM only binds to KRAS via its lipid tail but not the main body of the protein, Agamasu and team also show that CaM binds to both the active and inactive forms of KRAS. 

“CaM removes KRAS from the membrane by grabbing onto a part of the lipid tail and displacing it,” Agamasu said. “Showing how KRAS and CaM interact is important in understanding the regulation of KRAS.”

Additional Frederick National Laboratory authors: Troy Taylor, Simon Messing, Timothy Tran, Lakshman Bindu, Frank McCormick, Dwight Nissley and Andrew Stephen. 

By Mary Ellen Hackett, staff writer

Image: Biophysical Journal cover illustrating the FNL study.