On the front lines of our defenses against bacteria is the protein calprotectin, which "starves" invading pathogens of metal nutrients.
Vanderbilt investigators now report new insights to the workings of calprotectin including a detailed structural view of how it binds the metal manganese. Their findings, published online before print in the Proceedings of the National Academy of Sciences, could guide efforts to develop novel antibacterials that limit a microbe's access to metals.
The increasing resistance of bacteria to existing antibiotics poses a severe threat to public health, and new therapeutic strategies to fight these pathogens are needed.
The idea of "starving" bacteria of metal nutrients is appealing, said Eric Skaar, Ph.D., MPH, associate professor of Pathology, Microbiology and Immunology. In a series of previous studies, Skaar, Walter Chazin, Ph.D., and Richard Caprioli, Ph.D., demonstrated that calprotectin is highly expressed by host immune cells at sites of infection. They showed that calprotectin inhibits bacterial growth by "mopping up" the manganese and zinc that bacteria need for replication.
Now, the researchers have identified the structural features of calprotectin's two metal binding sites and demonstrated that manganese binding is key to its antibacterial action.
Calprotectin is a member of the family of S100 calcium-binding proteins, which Chazin, professor of Biochemistry and Chemistry, has studied for many years. Chazin and postdoctoral fellow Steven Damo, Ph.D., used existing structural data from other S100 family members to zero in on calprotectin's two metal binding sites. Then, they selectively mutated one site or the other.
They discovered that calprotectin with mutations in one of the two sites still bound both zinc and manganese, but calprotectin with mutations in the other site only bound zinc. The researchers recognized that these modified calprotectins especially the one that could no longer
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center