[Paleopsych] Finding may unlock secret to nerve growth factor

[Steve Hovland]

http://news-service.stanford.edu/news/medical/2004/may26/nerve.html
Researchers' discovery could pave way for development of drugs that alter 
nerve growth

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.