To fully appreciate how our bodies respond to a wide array of stimuli such as light and pain, a team of scientists, including Nobel Prize-winning scientists Robert Lefkowitz and Brian Kobilka, has determined the underlying architecture of a cellular signalling complex.
This complex, consisting of a human cell surface receptor and its regulatory protein, revealed a two-step mechanism. The findings provided structural images of a G-protein coupled receptor (GPCR) in action.
"It is crucial to visualise how these receptors work to fully appreciate how our bodies respond to a wide array of stimuli, including light, hormones and various chemicals," said Lefkowitz of the Duke University School of Medicine in the US.
Lefkowitz and Kobilka shared the 2012 Nobel Prize in chemistry for their discoveries involving GPCRs, which represent the largest family of drug targets for human diseases, including cardiovascular disorders, neurological ailments and various types of cancer.
The scientists visualised a complex of the protein beta arrestin, which is key for regulating these receptors, along with the receptor involved in the "fight-or-flight" response in humans.
"Arrestin's primary role is to put the cap on GPCR signalling. Elucidating the structure of this complex is crucial for understanding how the receptors are desensitised in order to prevent aberrant signalling," added Georgios Skiniotis, a professor at the University of Michigan in the US.
Once the authors had material available for direct structural visualisation, they used electron microscopy to reveal how the individual molecules of this signalling assembly are organised with respect to each other.
The researchers then combined thousands of individual images to generate a better picture of the molecular architecture.
They further clarified this picture by cross-linking analysis and mass spectrometry measurements.
The findings appeared in the journal Nature.
