Protein-membrane anchors have two domains; a ’key’ domain which binds to some part of the target molecule, and an ’anchor’ domain which is attracted to the non-polar cell membrane. A team from the University of Toronto Mississauga is using this strategy to block the STAT3 signalling pathway, which is implicated in certain cancers.
By Tyler Irving
Posted October 2011
In order to block the action of an enzyme, it’s usually necessary to create a molecule that binds to its active site. But a group of researchers at the University of Toronto Mississauga (UTM) have come up with a different strategy — they simply throw out an anchor.
STAT3 (from Signal Transduction and Activation of Transcription) is a protein that activates certain genes involved in cell differentiation, proliferation and survival. In cancer cells, this protein’s pathway is permanently turned on and turning it off is a big goal for drug makers. “Despite its clinical relevance to cancer, there is no easily targetable site on the surface of the protein and no STAT3 drug in the clinic,” says Patrick Gunning, professor in the Department of Chemical and Physical Sciences at UTM.
The team reasoned that because STAT3 is a macromolecular signalling protein that shuttles between the cytoplasm and the nucleus, preventing it from moving freely throughout the cell would be enough to block its action. They made the anchor by attaching a peptide sequence known to bind to STAT3 to various hydrophobic molecules, which are attracted to the non-polar environment of the cell membrane. The hydrophobic molecule that worked best turned out to be cholesterol. “We were quite amazed by the images that we got. We see complete anchorage of the protein to the cytosolic membrane,” Gunning says.
The team is now working on replacing the peptide binding sequence with a more robust molecule that will not degrade in the body. Gunning notes that the new strategy could work on other enzymes as well. “If we can inhibit any protein’s movement within the cell using a protein-membrane anchor, then we have the potential to stop its function and reverse its aberrant role.” The work is published in Angewandte Chemie.
Photo Credit: Patrick Gunning
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