The interferon receptor (blue and green) can distinguish different interferons (brown)
by how tightly they bind.

Image by the Garcia lab

Unlocking the Interferon Puzzle

Scientists show that interferon signaling depends on bond strength.

How can different interferon molecules bind to the same receptor and elicit vastly different responses? This conundrum has long puzzled scientists who study these signaling proteins. A study led by HHMI investigator K. Chris Garcia suggests the key may lie in how tightly the interferons bind to that receptor.

Interferons are protective chemicals that cells produce to combat cancer, viruses, and infections. It takes the combined effort of many different interferon molecules to get the job done, and each one activates a particular component of the body’s defense systems.

Garcia wanted to figure out how the 16 varieties of type I interferon trigger different cellular actions through just one cell surface receptor. He and his postdoctoral fellow Christoph Thomas at Stanford University School of Medicine used x-ray crystallography to deduce the three-dimensional structures of the receptor’s two subunits, IFNAR1 and IFNAR2, bound to two kinds of type I interferons, IFNα and IFNω.

Surprisingly, both interferon varieties bound the subunits in a similar fashion. The finding countered the prevailing notion that each kind of type I interferon would bind in a unique way.

To dig deeper, Garcia teamed up with researchers from the Weizmann Institute of Science in Israel and the University of Osnabrück in Germany. Collectively, they mutated the interferon amino acids responsible for binding to the receptor and found that although the locations of most contact points are constant from one interferon to another, the strength of the bonds varies. Thus, the receptor differentiates between interferon molecules by how avidly they attach at certain positions. The punch line is that chemistry, rather than ultrastructure, appears to functionally differentiate interferons.

As Garcia reports in the August 19, 2011, issue of Cell, manipulating the chemistry of the binding surfaces can endow one interferon with the functional properties of another. For example, replacing a single amino acid in IFNω with the one found at the same position in IFNα boosts the mutant IFNωs cancer-fighting ability, making it more like IFNα.

These findings provide an alternative to the long-standing “lock-and-key” model of receptor binding in which there’s only one way a molecular key can bind to, and activate, its receptor lock.

Scientist Profile

Investigator
Stanford University
Immunology, Structural Biology

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