Effects of a major drug target regulated through molecular 'codes'

July 27, 2017, Van Andel Research Institute
Rhodopsinarrestin. Credit: Parker de Waal, Xu Laboratory, Van Andel Research Institute

A team spearheaded by Van Andel Research Institute scientists has answered a long-standing question that may lead to more effective drugs with fewer side effects for diseases ranging from heart failure to cancer.

The findings, published today in Cell, reveal for the first time components of a G protein-coupled receptor (GPCR) named rhodopsin bound to a signaling molecule called arrestin, both crucial pieces of the body's intricate cellular communication network. The new discovery further refines a landmark 2015 Nature article that first described the structure of the two molecules in complex together.

"Our revised structure is like a roadmap with additional details and geographic features filled in," said VARI Professor H. Eric Xu, Ph.D., 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, to the ultimate benefit of patients around the world."

GPCRs are the largest group of , and act as information clearinghouses by linking up with either arrestins or other signaling molecules called G proteins to relay critical instructions for countless biological functions, including growth and hormone regulation. These characteristics, coupled with their location on the surface of the cell, make them attractive targets for drug therapy. An estimated 30 percent of all medications currently on the market target GPCRs.

"Since arrestins and G proteins mediate different cellular responses, developing drugs that activate only one of these two pathways may produce fewer side-effects for patients," said Karsten Melcher, Ph.D., a senior author on the paper and associate professor at VARI. "The insight provided by our expanded structure could go a long way in guiding the design of these therapies."

To determine their augmented structure, Xu Lab Senior Research Scientist Edward Zhou, Ph.D., reanalyzed more than 22,000 individual images collected for the original 2015 study using improved software not available at the time. It revealed three previously hidden molecular components called phosphoryl groups on rhodopsin and three corresponding pockets on arrestin that act as docking stations. The specific arrangement of these phosphoryl groups—known as phosphorylation codes—are required for rhodopsin to bind to arrestin, much like the combination to a safe. Once complete, this interaction initiates one branch of a complex cellular that regulates functions throughout the body.

"The big question then became, 'If this is happening with rhodopsin and arrestin, does it happen in all GPCRs?'" said Parker de Waal, a Van Andel Institute Graduate School student and member of Xu's lab. "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."

A tool to explore the prevalence of these codes across annotated GPCR data didn't exist, so de Waal created one. 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 says, are to investigate whether these findings hold true across all GPCRs and other that interact with arrestin.

"With biology, there's always more than one way of doing things," Xu said. "We want to follow those other avenues too in the hope that they help us further understand these critical mechanisms."

Explore further: How proteins find one another

More information: Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors, dx.doi.org/10.1016/j.cell.2017.07.002 , www.cell.com/cell/fulltext/S0092-8674(17)30773-0

Related Stories

How proteins find one another

February 22, 2017

Researchers from Charité – Universitätsmedizin Berlin have been studying two proteins that play a vital role in many bodily processes. The aim of the research was to establish how G-protein-coupled receptors (GPCRs) and ...

Researchers identify important signaling molecule

March 25, 2016

An international team of scientists have provided insights into the working of a "signaling molecule", which will provide new strategies for medicines in areas such as pain medication.

Imaging technique shows molecular machinery at work

June 8, 2017

New imaging methods that allow researchers to track the individual protein molecules on the surface of cells have been developed by Weill Cornell Medicine investigators. The results offer unprecedented insight into how cells ...

Recommended for you

A protein that self-replicates

February 22, 2018

ETH scientists have been able to prove that a protein structure widespread in nature – the amyloid – is theoretically capable of multiplying itself. This makes it a potential predecessor to molecules that are regarded ...

Newly designed molecule binds nitrogen

February 22, 2018

Wheat, millet and maize all need nitrogen to grow. Fertilisers therefore contain large amounts of nitrogenous compounds, which are usually synthesised by converting nitrogen to ammonia in the industrial Haber-Bosch process, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.