Collaborations, especially interdisciplinary ones, can lead to unexpected discoveries.
That's what Dr. Roland Strong, structural biologist in the Basic Sciences Division, realized when his laboratory solved the three-dimensional structure of an immune-system complex studied by immunologist Dr. Thomas Spies and colleagues in the Clinical Research Division.
Strong's group, using a technique known as X-ray crystallography, clarified the structures of two proteins whose interaction triggers an immune-system response to kill virus-infected cells.
The study, led by postdoctoral fellow Dr. Pingwei Li and published in the May issue of Nature Immunology, builds on Spies' identification of the MIC and NKG2D proteins and characterization of their role in the body's defense system.
While most protein interactions require that partners merge in a relatively fixed manner, much as a key fits a lock, one of the components in this immune-system pair, NKG2D, exhibits a promiscuity that is "virtually unprecedented in structural biology," Strong said.
"NKG2D can bind not only to different parts of its partner protein, MICA, but also to structurally different variants of MICA," he said. "That goes against what we know about typical protein-protein interactions."
NKG2D is a protein found on the surface of two types of immune-system cells, T cells and natural killer cells. Its role is to help them find unhealthy cells in the body - such as cancer cells or those infected by viruses - by looking for molecular clues, one of which is the cell-surface protein MICA.
When a cell is stressed, such as by infection with a pathogen, it synthesizes MICA, which studs the surface of the cell and acts as a distress signal.
Recognition of MICA by immune cells bearing NKG2D triggers a cascade of events that ultimately result in the destruction of the stressed cell.
Strong's group discovered that a pair of NKG2D molecules binds to a single molecule of MICA. The two copies of NKG2D are identical, and their association produces a large structure of two mirror-image halves.
What is striking, Strong said, is that similar surfaces of this mirror image can bind to different portions of MICA.
"Typically, a protein has a unique and specific interaction with a protein that it binds," he said. "In this case, we are seeing identical surfaces having the capacity to bind very tightly to two surfaces of MICA that look very different."
What's more, he said, the pair of NKG2D proteins also can bind to variants of MICA that look significantly different from the typical version.
Genetic variation among individuals may result in the production of proteins with structural differences. Sometimes the variation is of little consequence, but in other situations it can be dramatic enough to cause profound changes in three-dimensional structure that can alter a protein's function.
In the case of MICA, significant changes to the surface of the protein would be expected to disrupt its interaction with NKG2D. In fact, Strong said, not only can NKG2D bind to human variants of MICA, it also can bind to the cow version of the protein. "The question we'd like to answer is, how does NKG2D tolerate the differences in these structures?"
The answer to this question may help scientists understand what structural components of the complex are central to its ability to function correctly in an immune response.
Strong's main research interest is in molecular interaction and recognition between cells. The immune system, he said, "is a fantastic model for this. There is an incredibly dense network of cell-surface molecules on immune cells that are critical for their ability to respond. If we really want to understand protein recognition, this is the system to look at."
Just as the NKG2D study has opened up new research opportunities for Strong's lab, Spies, a coauthor on the paper, sees great benefit from the collaboration.
"It is satisfying to see the structure of a molecular complex that has been studied functionally but has not been 'visible' at such resolution in the past," he said.