Building on their own seminal GPCR research from 2015, scientists from the Van Andel Research Institute (VARI) have revealed three new lock-and-key structures of phosphoryl groups on the photosensitive GPCR rhodopsin and three corresponding pockets on arrestins that act as docking stations. The specific arrangement of these phosphoryl groups—known as phosphorylation codes—are required for arrestin to bind to rhodopsin. The work was published this week in Cell.
“If this is happening with rhodopsin and arrestin, does it happen in all GPCRs?” Parker de Waal, a Van Andel Institute Graduate School student and member of VARI professor H. Eric Xu’s lab, asked. “Our results indicate that these codes—these specific sequences of phosphoryl groups—are found in whole or in part in most GPCRs. The findings help elegantly address a longstanding question within our field; why certain GPCRs bind arrestins better than others can now be explained by the existence of phosphorylation codes.”
For this study, de Waal created a tool to explore the prevalence of the phosphorylation codes across annotated GPCR. Part web GUI and part Python-based command line tool, PhosCoFinder allowed the team to rapidly search through the total set of all known GPCRs and predict potential phosphorylation codes.
As expected, more than half of the 825 GPCRs scanned by PhosCoFinder were found to contain phosphorylation codes within their C-terminal tail, a part of the GPCR that helps transfer information from the cell’s environment to the inside of the cell. Most of the remaining GPCRs also were found to have codes; however, they were located in areas other than their C-terminal tails, possibly affecting the way they bind to arrestins.
The next steps, Xu said, are to investigate whether these findings hold true across all GPCRs and other cell surface proteins that interact with arrestin.
“Our revised structure is like a roadmap with additional details and geographic features filled in,” explained Xu, the lead author of the new study as well as the 2015 article. “For years, the field has sought to answer exactly how arrestins interact with GPCRs. We hope the answer provided by our work, in the context of rhodopsin, will fuel new research and the design of better medications.”
Image: Rhodopsin-arrestin. Courtesy of Parker de Waal, Xu Laboratory, Van Andel Research Institute