Cancer researchers find key protein link
A new understanding of proteins at the nexus of a cell’s decision to survive or die has implications for researchers who study cancer and age-related diseases, according to a new study part-funded by the European Research Council.
Biophysicists at Rice University in Texas, United States, used experiments and computer analysis of two key proteins to reveal a previously unknown binding interface that could be addressed by medication. The proteins are Bcl-2, well known for its role in programmed cell death, and NAF-1, a member of the NEET family that binds toxic clusters of iron and sulphur.
It’s now known that the two interact as a major determinant in the cell processes of autophagy and apoptosis. An ability to uncover binding sites on the proteins that send the cell one way or the other opens a path toward the regulation of those processes, according to José Onuchic, professor of physics and astronomy at Rice University.
Pockets and folds in proteins exist to bind to other molecules and catalyse actions in a cell in signalling pathways. The ability to block a specific binding site or to enhance a desired interaction is critical to drug design, Onuchic noted.
“In our early work we have shown the link between NEET proteins and cancer. Now we can understand the molecular details of how these interactions are governed,” Onuchic added. “Others have shown that NAF-1 is up-regulated in cancer cells, which leads us to believe that cancer may hijack control over the expression of this protein. This affects the cell’s system of checks and balances. Understanding NAF-1 gives us a better idea of how to approach treatment.”
Onuchic said the researchers found that NAF-1 binds to two specific regions of the protein Bcl-2 and that Bcl-2 binds to the NAF-1 groove formed between the beta cap and iron-sulphur cluster binding domains; the strongest coupling is at the cluster binding domain and some contacts of interest are at the top of the beta-cap domain. Since the iron-sulphur cluster is the functional entity involved in NAF-1 activity, these findings clearly indicate that Bcl-2 interaction with NAF-1 affects its activity.
