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Tagged for arrest: “Barcode” determines receptor’s fate

Receptor proteins serve as the “eyes and ears” of the cell. The largest receptor family are the so-called G protein-coupled receptors. They respond to highly diverse stimuli ranging from photons to hormones and odorants. Researchers at the University of Basel have discovered a unique recognition pattern that works like a barcode and tags the receptor for desensitization. By this mechanism, signaling in cells is rapidly switched off when it is no longer needed.

06 June 2023 | Katrin Bühler

Illustration of a G protein-coupled receptor
Receptors of the G protein-coupled receptor family contain a specific recognition pattern that determines their fate. (Artwork: Anna Golynski)

Odors, light, hormones and a tremendous variety of signaling molecules are recognized by a large family of cell receptors, known as G protein-coupled receptors (GPCRs). They are located on the cell surface and transduce signals into physiological outputs, for example, a rapid heartbeat triggered by fear or inflammation caused by infections. Due to its crucial role in many vital processes, this receptor family is implicated in a wide range of diseases, such as depression, cancer, inflammation, or cardiovascular diseases.

Humans have more than 800 GPCRs in their body. They are the targets of more than one third of all approved drugs, comprising the most important and successful therapeutics against many diseases, including AIDS and hypertension. The ever-increasing understanding of the exact molecular mode of action of GPCRs is currently fueling the development of many completely new therapeutic avenues.

What is not well known at present is how active GPCRs are stopped in their action when their signal is no longer needed. In collaboration with researchers at the Indian Institute of Technology, the team led by Professor Stephan Grzesiek at the Biozentrum, University of Basel, has now identified a key recognition motif that decides the fate of the activated receptor for desensitization and possible degradation. Their findings have recently been published in “Molecular Cell”.

“Barcode” for receptor recognition

For our body, it is indispensable to turn off active receptors and thus stop signaling. For example, the heart rate must return to normal after the danger has passed. “The turn-off and removal of the hundreds of different GPCRs are accomplished by only two intracellular proteins, known as arrestins – this name comes from the word ‘arrest’,” explains Dr. Polina Isaikina, first author of the study. “We have now identified a biochemical recognition pattern, a so-called phosphoresidue cluster, responsible for robust arrestin recruitment in many GPCRs.” This specific pattern works like a barcode and determines whether the receptor will be degraded or recycled in the cell.

Original publication

Polina Isaikina, Ivana Petrovic, Roman P. Jakob, Parishmita Sarma, Ashutosh Ranjan, Minakshi Baruah, Vineet Panwalkar, Timm Maier, Arun K. Shukla, Stephan Grzesiek.
A key GPCR phosphorylation motif discovered in arrestin2•CCR5 phosphopeptide complexes.
Molecular Cell (2023), doi: 10.1016/j.molcel.2023.05.002

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