Sanford-Burnham has a long history with proteins of the so-called Cas family, particularly one member called p130Cas. For more than a decade, some of our top researchers, including Kristiina Vuori, M.D., Ph.D., Erkki Ruoslahti, M.D., Ph.D., and Elena Pasquale, Ph.D., have studied the biology of these proteins and the role they play in cancer. And they made several groundbreaking findings.
One of these was the co-discovery of a family of novel cell-regulating proteins that interact with Cas proteins, called the NSP family. When Cas and NSP proteins get together, they help a cell migrate or invade surrounding tissues—processes that can be either beneficial, as when immune cells mature, or harmful, as when a cancer cell metastasizes. Furthermore, one particular pair of Cas and NSP proteins were found to cause breast cancer cells to become resistant to anti-estrogen drugs such as tamoxifen, one of the major challenges in fighting this devastating disease.
While biologists were able to make significant strides in understanding these proteins and their functions, questions remained. Nobody could put their finger on exactly how these proteins actually get together to do the work they do, leaving scientists with questions like: What do Cas proteins and NSP proteins look like in 3D? What does the complex look like when two of these proteins are bound together? And what does that all mean for how they work?
Structural biologists Stefan Riedl, Ph.D. and Peter Mace, Ph.D. recently answered several of these perplexing questions. In a paper published November 13 in Nature Structural & Molecular Biology, Riedl and Mace, along with Pasquale and Yann Wallez, Ph.D., pulled off what seemed like the impossible: they solved the co-structure of one NSP-Cas pairing, the duo NSP3 and p130Cas, as well as the structure of another NSP by itself, a protein known as the breast cancer anti-estrogen protein 3.
And with this feat came a big surprise about NSP protein function—it doesn’t actually do what everyone assumed it does. Scientists can make predictions about a protein’s function based on its sequence of amino acids—the building blocks that make up a protein—which is generally a very powerful approach. Yet, to obtain certainty, one has to obtain experimental data, which Riedl and Mace did using a method called X-ray crystallography.
In this case, sequence information had shown that the “business-end” of NSP proteins looks like an enzyme that acts as a molecular switch, turning cellular communication proteins on or off. Only the 3D structures solved by Riedl and Mace show that this function is impossible—the business end is folded over in a “closed” position. Instead, it turns out that this closed position is what lets the NSP business-end carry out its true function—binding p130Cas.
“This was absolutely unexpected. Everyone assumed that NSP3 was in an open, active form,” said Riedl. “What often happens in structural biology is that you see how things work on a molecular scale and discover something new, which then allows researchers to better understand cellular communication systems and their involvement in disease on a cellular level.”
Sanford-Burnham collaborations spanning 15 years—from early discovery to biological function to 3D structure— keep bringing us new surprises about the human body.
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Original paper:
]Mace PD, Wallez Y, Dobaczewska MK, Lee JJ, Robinson H, Pasquale EB, & Riedl SJ (2011). NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling. Nature structural & molecular biology, 18 (12), 1381-7 PMID: 22081014
