Sligar's nanodisc technology sets sights on advancing cellular function

Stephen Sligar, a faculty member in the 3-D Micro- and Nanosystems group at Beckman, focuses on using novel technologies in order to understand the mechanisms of biological function at the molecular and cellular level. Sligar is currently using nanodisc technology in a number of projects aimed at advancing our understanding of cellular function, as well as aiding development of drug targeting methods.

In a recent paper in the Proceedings of the National Academy of Sciences titled "Nanodiscs separate chemoreceptor oligomeric states and reveal their signaling properties" Sligar and his collaborators report on using nanodiscs - which are composed of a phospholipid bi-layer encircled by a membrane scaffold protein - to control the oligomerization state of the protein that is incorporated into it.

The nanodiscs, about 10 nanometers in diameter and good for manipulating membrane proteins, help give the researchers insight into cellular activity such as the interactions between receptors and signaling pathways.

"We were able to ask a question using these nanodiscs as to which of these particular signaling activities require which particular oligomeric structures, whether it's a monomer, a dimer, or a trimer of dimers," Sligar said. "By doing that we can incorporate these receptors into the nanodisc system and then separate them out based on their stoichiometry.

"Basically what this allows us to do is to separate out which oligomeric state of which receptor is responsible for which signaling event."

Sligar, the I.C. Gunsalus Endowed Chair Professor in the Department of Biochemistry, said the paper is part of a broader initiative to use nanostructures to advance knowledge about macromolecules. One potential benefit of this research line could involve drug targeting. Sligar said most drugs target a receptor called the G protein-coupled receptor (GPCR), of which there are hundreds in the human genome but only a dozen that are currently targeted by therapeutic drugs. The group's nanodisc technology could prove extremely useful in improving those numbers.

"The ability to control the oligomerization state and be able to study and define which signaling properties go with which oligomeric state is a very enabling discovery for ultimately defining particular drug targets for humans," Sligar said.

To read the PNAS paper, click here