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A tale of two tails

Memphis, Tenn. - April 27, 2022

St. Jude researchers Daniel Terry and Scott Blanchard

Scott Blanchard, Ph.D., and Daniel Terry, Ph.D., of the Department of Structural Biology

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.

Read the news release

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