‘Shape-shifting’ protein could form basis for universal biohazard sensor

See full image. Ribbon diagram of the prediction of the protein switch structure. Purple indicates “receptor” part of the protein switch.Yellow represents the target molecule and also the region where the catalytic reaction takes place. Light blue marks the enzyme part of the switch that catalyzes the chemical reaction. Credit: Monica Berrondo/Gray Lab/JHU

Biosensors—devices that convert biological responses into readable signals— detect tiny amounts of single target molecules. Single molecule detection systems form the foundation of biosensors, like the ones used to recognize biohazards such as anthrax. A better biosensor, however, would be able to change to detect not one, but hundreds of different target molecules.

Researchers from Johns Hopkins Institute for NanoBioTechnology (INBT), collaborating with researchers from Northrop Grumman, will receive $1.5 million over three years from the Defense Threat Reduction Agency (DTRA) to study an unusual protein switch that can “shape-shift.“ The switch could become part of a universal platform for an improved biosensor.

Protein switches consist of a receptor protein attached to an enzyme. “The receptor protein possesses a binding pocket with a particular shape and size that will accept only one type of target molecule. When a target molecule fills the binding pocket, the receptor protein often changes shape,“ says Marc Ostermeier, associate professor of Chemical and Biomolecular Engineering.

This altered shape triggers the enzyme linked to the receptor protein to start a chemical reaction, which produces something that can be measured. The measured product is converted into a readable signal, such as turning on a light or sounding an alarm. In the proposed biosensor, the team will use protein switches with a recognition element that can be readily changed to detect a variety of target molecules.

“It is unclear which receptors will be useful for building switches and biosensors,“ says Konstantinos Konstantopoulos, professor and chair of the Department of Chemical and Biomolecular Engineering in the Whiting School of Engineering. So the Hopkins/Northrop Grumman group will be testing many different receptors and learning how they recognize their target, why they behave as switches, and which will make the best sensors.

The concept, says principle investigator Peter Searson, takes the approach that all existing proteins can be viewed as an extensive list of parts from which switches can be assembled. Searson is the Whiting School’s Reynolds Professor of Materials Science and Engineering and director of INBT.

“Our switches will offer an excellent platform for an extensive study, since we have the ability to evaluate, in parallel, millions of switch variants,“ added Searson. Knowledge gleaned from these fundamental studies, Searson says, could provide the basis for a new line of “smart“ biosensors that would not only detect many different target molecules, but might be able to remember the proteins it encounters as well.

John C. Schmidt, Chemical, Biological, Radiological, Nuclear, Explosive (CBRNE) Defense Director and Enterprise Technical Executive at Northrop Grumman Electronic Systems (NGES), and Matthew Lesho, NGES biomedical engineer, are collaborating with the Hopkins team. Schmidt and Lesho are alumni of Johns Hopkins University, and Northrop Grumman is a member of INBT’s Industrial Affiliates Program.

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Story by Mary Spiro

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