Scientists at St. Jude and Columbia University/New York State Psychiatric Institute are studying how information transfers from outside to inside a cell. Their work may influence drug development.
The scientists are looking at G-protein coupled receptors (GPCRs). GPCRs are found on cell membranes. One-third of all drugs target GPCRs. When activated, GPCRs send signals to the inside of the cell. β-arrestins are proteins that bind GPCRs to stop this signaling and trigger downstream signaling pathways. This interaction involves the tail region of the GPCR protein. The tail docks into a groove on β-arrestin.
When β-arrestin is not engaged with a GPCR, a part of β-arrestin occupies the groove. This part of β-arrestin is called the C-terminal tail. Scientists wanted to see how the C-terminal tail releases to make room for the GPCR tail. To do so they used single-molecule fluorescence resonance energy transfer (smFRET).
“Single-molecule imaging is a way to directly measure molecular-scale conformational [shape] changes. It is very insightful and often is more easily interpreted than other approaches,” said Scott Blanchard, PhD, Structural Biology.
The group’s findings show that the resting β-arrestin exists in a stable, autoinhibited state. In this state, the C-terminal tail binds tightly to the groove. For the C-terminal tail to release and make room for the GPCR tail, the GPCR must be activated so that it “tickles” the β-arrestin and triggers the release. smFRET allowed the researchers to monitor these events.
The findings appeared in Cell.