Researchers have identified a protein that is different between healthy and cancerous cells, offering a potential target for therapeutic interventions.
Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This “PIP-stop” releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces.
Michael Overduin, a University of Alberta cancer researcher and professor of biochemistry, led an international team in this new study, which looked at a sorting nexin protein .
The research team discovered a modified protein inside cancer cells. This protein, which they named PIP-stop, acts a bit like a “stop sign”, preventing proteins from interacting with lipid molecules called PIP. The protein is found in excessive amounts in leukemia, lymphoma and neuroblastoma cells. This could disrupt normal protein function and is a potential target for interventions that inhibit PIP-stop.
During the study, the research team investigated the structure of a sorting nexin protein, which is responsible for sorting proteins and directing them to the correct locations within a cell. They used high-powered magnets to detect the signals from within atoms inside this protein structure.
In doing this, they discovered PIP-stop and how it prevented the sorting nexin protein from working. Functionally, PIP-stop is a phosphate that, when added to the protein surface, binds the PIP lipid and controls how proteins attach to membranes.
The researchers discovered that in samples from cancer patients, there were excessive amounts of PIP-stop, which could lead to disrupted protein sorting and encourage uncontrolled cell proliferation. They also found that similarly high levels of PIP-stop were present in a variety of other proteins involved in other forms of cancer.
The researchers’ next step will be to design inhibitors that target the overactive kinases that produce PIP-stop as the basis of a therapy to halt the progression of cancer, which is especially good news for cancers that currently lack effective treatment options.
Researchers are discovering more and more ways to potentially derail cancer and shut it down; this new discovery is yet another weapon to add to the growing arsenal in the fight against cancer.
 Overduin. M, et al. (2018) Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting. Nature Communicationsvolume 9, Article number: 993 doi:10.1038/s41467-018-03370-1