Wellcome Trust Sanger Institute scientists have developed a new large-scale method to identify the interactions between proteins that are a major target for therapeutic intervention.
The novel method can identify the weak, short-lived interactions that are characteristic of cell responses to cues from the environment or from within the body.
Cell surface proteins are targets for many drugs and are central to many processes of cell regulation, such as some cancer therapeutics, diabetes, and growth. The team hope the method will uncover many important interactions that are invisible to current detection methods.
Many proteins act as molecular switches, responding to signals and activating specific genes or specific cell processes. Using biochemical tricks to increase the chances of detecting the transient and weak, but potentially important, interactions, the scientists describe 17 new pairs of interactions in mammalian cells.
"If a genome is the code for life, interactions between proteins are the communications system - the internet of our bodies," Explains Dr Gavin Wright, Junior Investigator at the Wellcome Trust Sanger Institute. "The challenge we face is that current methods cannot efficiently detect interactions at the place where communication starts: the cell surface, nor can they reliably detect transient weak interactions.
"Our new method transforms the large-scale search for these important interactions."
Unlike DNA sequencing, where methods are common to all organisms, there has been no one approach that gives a global fit for all diverse protein-protein interactions. The new method, called AVEXIS, should be applicable to interactions at the cell surface in many organisms.
Drug targets are often proteins at the surface of the cell since they are easily accessible to drugs in contrast to proteins within our cells. Unfortunately, the current catalogue of known protein interactions is biased away from these proteins simply because there was no efficient method to examine them. Effectively, a swathe of clinically important targets is invisible to research.
"AVEXIS now allows us to scale the hunt for biologically and clinically important protein-protein interactions," continues Dr Wright. "These interactions are like Velcro® - each hook can bind only weakly, but together, they can have a very strong effect. We increased the strength by gathering the proteins together, as in a small scrap of Velcro®."
The team identified previously undescribed interactions in a class of proteins called the immunoglobulin superfamily: this group of proteins shares properties that are important to allow cells to respond to their environment, talk to one another and stick together. Using human proteins and zebrafish as a model, the Sanger Institute researchers looked at interactions between 110 proteins in this superfamily - a total of more than 6000 experiments.