By MITZI BAKER

Cells communicate through an intricate system of locks and keys -- receptors on cell surfaces and ligand molecules -- that allow the transmission of very specific information across their membranes.

Researchers at the School of Medicine have just discovered an unexpected new type of lock-and-key mechanism that provides a critical step in reproducing nerve growth factor, crucial to all aspects of nerve formation and function.

The information revealed can now be directly applied to design a drug to treat neurodegenerative conditions such as Alzheimer's disease or spinal cord injuries.

Nerve growth factor, or NGF, is one of the most important molecules in the nervous system, said Chris Garcia, PhD, assistant professor of microbiology and immunology and of structural biology.

NGF and its family members called neurotrophins not only control the development of the nervous system in the embryo but also the maintenance of nervous tissue and neural transmission in the adult.

Researchers Xiao-lin He (left) and Chris Garcia sit in front of a computer screen that shows an electron density map created by X-ray imaging that helped derive the structure of nerve growth factor. Their research "unlocks" an important step in reproducing the growth factor, which plays a critical role in nerve formation and function. Photo: Mitzi Baker

NGF plays a role in many nervous system problems such as neural degeneration in aging, Alzheimer's disease and neural regeneration in spinal cord injuries and other damage to neural tissue. It also may factor into mood and other psychological disorders.

NGF's fundamental importance in the nervous system, Garcia said, made it a compelling puzzle to try to solve in his lab, which focuses broadly on how information is communicated across membranes using receptors and ligands, the locks and keys of molecular biology. Interestingly, he added, one of the receptors for NGF is also used by the rabies virus to gain entry into cells, stimulating interest in their lab which has a focus on molecules involved in infection and immunity.

"A lot of companies have tried for many years to make a drug out of NGF and it just hasn't worked very well because basically no one has really known what the mechanisms are for receptor activation," he said. "I think the significance of our result is that now we have an atomic model of this system that begins to clarify a lot of the confusing functional data."

Garcia and a postdoctoral scholar in his lab, Xiao-lin He, PhD, published their findings of the three-dimensional structure of NGF bound to its receptor earlier this month in Science.

The main question that hadn't been answered until now is how a molecule with two symmetrical parts like NGF could simultaneously activate two different receptors on its surface -- called p75 and Trk -- required for its signal.

The question that had been a conundrum for researchers in neurobiology for 15 years was "how does NGF specifically select one of each type of receptor instead of two of the same?"

"No matter what we found, we knew that it was going to be new and unprecedented," said Garcia.

In a mechanism that could be right out of the world of "Harry Potter," the key inserted into one of the locks morphs such that the shape of the combined parts then fits with another type of lock.

Garcia and He discerned this unusual feature of the interaction by using X-ray imaging techniques confirmed by biochemical methods.

"The result was a complete surprise," said He, who has been studying the NGF signaling system for about a year. He explained that since NGF is composed of two identical chains of protein, it would be logical that it binds the two identical chains of the p75 receptor. But it only attaches to one chain.

The researchers found that after NGF connects with one of the p75 protein chain, it changes shape such that a second receptor of the same kind cannot fit. What that does, said Garcia, is allow the other NGF receptor, Trk, to bind on the other side and form a three-way signaling complex.

Garcia said neurobiology researchers are also surprised by the finding, which has caused controversy about its meaning. Garcia and He's detailed structural data can now be used by others in the field as a template for further experiments.

"Our data is going to stimulate a lot of science to figure out what its significance is," Garcia said.

In terms of the straightforward goal of creating a drug that simulates or blocks the actions of NGF binding to its receptors, Garcia said, "It's all there. We've got it. What a drug company needs is in that structure right now and they don't need to know anything else."

This research is supported by a fellowship from the Paralyzed Veterans of America, Spinal Cord Research Foundation; the American Heart Association; the Christopher Reeve Paralysis Foundation; the Keck Foundation; and the National Institutes of Health.