New molecular structure offers first picture of a protein familyvital to human health

Their work, published online May 31, 2012, in Science Express, reveals an unexpected three-dimensional shape that offers clues tohow Wnt proteins function and clarifies the nature of its Frizzledreceptor target for drug developers working to design anti-Wnttherapies for cancer and other diseases. “Having finallygained structural access to Wnts, I think this is going to open upa whole new era in molecularly dissecting the role of Wnt proteinsin biological processes,” says Garcia. Wnt proteins were discovered 30 years ago by Harold Varmus, thecurrent director of the National Cancer Institute, and Roel Nusse,who is now an HHMI investigator at Stanford University. Theyobserved that Wnt1 , the gene for a Wnt protein, was very active in breast cancercells from mice.

Over the past decades, researchers have shown thatWnt proteins play key roles in embryonic development, tissueregeneration, bone growth, stem cell differentiation, as well asmany human cancers. In essence, Wnt proteins help give cells theiridentity and tell them how to behave. “This is one of the most important ligand-receptor systems inboth human and invertebrate biology. Wnts cut across every field,which is why I got involved. But many excellent groups have triedto express them in the lab and solve their structures, so werealized that something non-intuitive would be required to crackthe problem,” says Garcia.

In 2003, Nusse’s team found out why scientists who had been tryingto isolate Wnt proteins had been plagued with so many difficulties:the proteins contained lipids, fatty molecules that prevent theprotein from dissolving in water-based solutions. Scientistsrealized they could stabilize the protein by instead keeping it inmixtures that contained detergents, helping pave the way for aplethora of biochemical experiments on isolated Wnts. But suchdetergent-containing mixtures still present obstacles forcrystallizing and visualizing proteins by structural analysistechniques; simply put, the detergents get in the way. “This really causes a great deal of difficulty in working withthese proteins,” says Garcia. But he and Janda had an idea:what if they expressed both a Wnt protein, and the receptor itbound to in the same cell? Perhaps, they thought, the receptorwould shield the Wnt protein’s exposed lipid, making it able todissolve in the solution they needed. Dual Sim Quad Band Unlocked Phone

The technique worked — they were able to produce Wnt8 bound toFrizzled-8, one of 10 Frizzled receptors that the 20 Wnt proteinsbind to to carry out cellular effects. “It’s one of the most unusual protein structures I’ve everseen,” says Garcia. “It looks like a crab with its twopinchers reaching around and grabbing the Frizzled receptor. Whenwe originally solved this, we could see no relationship between thestructure of Wnt8 and any other structure that has ever beendescribed. However, we are beginning to see the evolutionaryorigins of the Wnt fold. Portable Speaker For Iphone Manufacturer

This story is developing.” Garcia expects the other Wnt proteins likely have similarstructures, with the respective Frizzled receptors shielding thelipid attached to the protein, meaning their method should work onother Wnts. He now wants to delve into those structures, answeringquestions about which Wnt-Frizzled pairs are responsible for whatbiological roles, how co-receptors bind to the pairs, and how thestructure can be changed to optimize the interactions. “What we can see now are some clues in the structure as to whyWnts are so hard to express, because of the exposure of thelipid,” says Garcia. “So now we can think about ways toremodel the protein that will solve the expression problem withoutaltering function.” But it’s not just basic science of Wnts that gets a boost with thenew method for solving their structure, and the new structuraldata. China Low Cost Dual Sim Phones

Wnts have long been considered a potential drug target forcancers, as well as other diseases. Knowing the structure providesa huge advantage when trying to develop compounds that will bind toWnts. “There are already some drugs companies that have beendeveloping anti-Wnt and anti-Frizzled antagonist antibodies asdrugs,” says Garcia. “But they’re been working in thedark, with no knowledge of structure.

So I really think this willopen up a whole new era for not only of basic biology on theseproteins, but also for their therapeutic potential. We arecurrently attempting to engineer Frizzled-specific Wnts in order tobetter understand the role of a particular Wnt in a biological anddisease process, as well as assess the efficacy of selectivelyblocking or activating Wnt signaling pathways.”.


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