DURHAM, N.C. -- A team of scientists from Duke Medicine, the University of Michigan and Stanford University has determined the underlying architecture of a cellular signaling complex involved in the body's response to stimuli such as light and pain.
This complex, consisting of a human cell surface receptor and its regulatory protein, reveals a two-step mechanism that has been hypothesized previously but not directly documented.
The findings, reported on June 22, 2014, in the journal Nature, provide structural images of a G-protein coupled receptor (GPCR) in action.
"It is crucial to visualize how these receptors work to fully appreciate how our bodies respond to a wide array of stimuli, including light, hormones and various chemicals," said co-senior author Robert J. Lefkowitz, M.D., the James B. Duke Professor of Medicine at Duke University School of Medicine and Howard Hughes Medical Institute investigator.
Lefkowitz is co-senior author with Georgios Skiniotis, Ph.D., the Jack E. Dixon Collegiate Professor at the Life Sciences Institute at the University of Michigan, and Brian K. Kobilka, M.D., the Helene Irwin Fagan Chair in Cardiology at Stanford University School of Medicine. Lefkowitz and Kobilka shared the 2012 Nobel Prize in Chemistry for their discoveries involving GPCRs.
GPCRs represent the largest family of drug targets for human diseases, including cardiovascular disorders, neurological ailments and various types of cancer. The protein beta arrestin is key for regulating these receptors, and the authors have visualized a complex of the protein beta arrestin along with the receptor involved in the "fight-or-flight" response in humans.
"Arrestin's primary role is to put the cap on GPCR signaling. Elucidating the structure of this complex is crucial for understanding how the receptors are desensitized in order to prevent aberrant signaling," Skiniotis said.
|Contact: Rachel Harrison|
Duke University Medical Center