Neurons are the basic functional unit of the nervous system. They are specialized cells responsible for all sensation and direction of movement in the body. Stimulated by NGF, each of these nerve cells extends an axon or dendrite projection that connects it to other neurons, muscle, or skin, and these projections provide the wiring for information sent between the brain and the spinal cord. Many of these connections between neurons and other tissues are also necessary for the continued survival of these cells. Neurons that are lost through aging, disease, or injury are unable to be replaced because most neurons are not able to divide to produce new neurons.

Neurotrophins are a family of proteins essential to the nervous system. Each neurotrophin can signal through two different types of cell surface receptor—the Trk receptor, tyrosine kinase, and the p75 neurotrophin receptor, which may have an important role in the control of axonal regeneration. During development of the brain, the binding of neurotrophins to their receptors is necessary to match the correct number of neurons with their targets. NGF also regulates axonal and dendritic growth, the formation of synaptic structure and connections, and neurotransmitter release. Neurotrophins are capable of promoting neuronal cell survival, or cell death, depending on the environment. Alterations in neurotrophin levels may underlie several medical conditions, including pain, depression, obesity, and disorders in nerve regeneration, learning, and memory.

Structure of the NGF–p75 complex. p75 binds along one side of the nerve growth factor (NGF) homodimer.

The Stanford researchers provided a detailed glimpse of how NGF binds to the p75 receptor, creating a three-dimensional atomic model that shows how a molecule with two symmetrical components, such as NGF, can simultaneously activate two different receptors on its surface. For the last fifteen years, neurobiologists have wondered how NGF specifically selects one of each type of receptor, p75 and Trk, instead of two of the same type.

Receptors and ligands are the locks and keys of molecular biology, allowing the transmission of specific information across cell membranes. The researchers showed that the NGF key combines with the p75 lock in a 2:1 ratio. When this binding occurs, a second p75 interaction is prevented—essentially, the NGF key changes shape after it enters the lock. This allows the other NGF receptor, Trk, to bind on the other side of the NGF molecule, forming a three-way signaling complex.

The researchers determined the structure by imaging crystals of the molecular complex of NGF with its low-affinity neurotrophin receptor, p75, using x rays produced at ALS Beamline 8.2.1, and refined the structure to a resolution of 2.4 angstroms. This dimension is about 100,000 times smaller than a cell—a resolution that's critical for an accurate picture of how the thousands of atoms in the neurotrophin-receptor structure are assembled.

With the definition of this crystal structure, drug companies can now work on stimulating or blocking the actions of NGF, potentially repairing the damage done by degenerative diseases of the brain.

Research conducted by X. He and K.C. Garcia (Stanford University).

Research funding: 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. Operation of the ALS is supported by the U.S. Department of Energy, Office of Basic Energy Sciences.

Publication about this research: X. He and K.C. Garcia, "Structure of Nerve Growth Factor Complexed with the Shared Neurotrophin Receptor p75," Science 304, 870 (2004).

ALSNews Vol. 246, October 27, 2004