New Images of Cancer Protein Reveal Potential New Drug Target
Researchers at Columbia University Vagelos College of Physicians and Surgeons have captured the first atomic-level images of Wnt, a protein commonly disrupted in cancer, in complex with its specific carrier WLS, and in the process have uncovered a potential new drug target.
Wnt proteins act as important signals that regulate stem cells and growth during development and control the identities of other cells.
Despite their importance in cancer and other diseases, little is known about the way Wnt proteins travel through the cell’s intracellular compartments to the outer membrane, where they are thought to be secreted to reach neighboring cells. A better understanding of these details could lead to new therapies.
Uncovering the 3D shapes of proteins can provide important insights, so the researchers, led by Rie Nygaard, PhD, a postdoc in the laboratory of Filippo Mancia, PhD, and colleagues at Duke-National University of Singapore turned to single-particle cryo-electron microscopy.
Nygaard, Mancia, and their colleagues first obtained images of millions of individual Wnt proteins attached to Wntless, its specific carrier that ferries Wnt from the endoplasmic reticulum through the intracellular compartments after Wnt is made and a bulky lipid is attached to it. By sorting and combining these images, Nygaard created a single high-resolution 3D structure of the Wnt bound to Wntless.
The new high-resolution structure solves one long-standing question about Wnt’s journey. Because of the lipid appendage, Wnts are very hydrophobic and do not easily mix with the watery interior of the cell. The new images reveal a large cavity inside Wntless, directly connected to the membrane, which appears to shield Wnt’s lipid appendage from the aqueous cytoplasm.
For cancer researchers, the importance of the Wntless structure and its cavity lies in the resemblance to G-protein coupled receptors and their ligand (and druggable) binding sites.
“There is already a lot known about G-protein coupled receptors and how to make drugs that target them,” Nygaard says, “suggesting that this could be a potential drug target for cancer drugs.”
The structure also revealed that the two proteins are tightly bound to each other, suggesting that Wnt is not simply released when the complex reaches the membrane.
Future studies should reveal more details and, potentially, new drug targets.
"This is the first atomic level snapshot of this process which is essential to biology and is a substantial advance in our understanding of how Wnt makes its journey,” Mancia says. “This is only the first snapshot, but there will be more to come, along with more insights.”
The results were published online Dec. 23 in Cell in a paper titled “Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion.”
The images were obtained at the Columbia University Cryo-Electron Microscopy Center.
Filippo Mancia, PhD, is associate professor of physiology & cellular biophysics at Columbia University Vagelos College of Physicians and Surgeons.
Other authors: Jia Yu (Duke-NUS Medical School); Jonathan Kim, Daniel R. Ross, Giacomo Parisi, and Oliver B.Clarke (all Columbia University Vagelos College of Physicians and Surgeons); and David M.Virshup (Duke-NUS Medical School).
This work was supported by the U.S. National Institutes of Health (grant R35 GM132120) and the Singapore Ministry of Health’s National Medical Research Council (Singapore Translational Research Award MOH-000155).
The authors declare no competing interest.