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How GPCR Phosphorylation Patterns Orchestrate Arrestin-Mediated Signaling.

Naomi R Latorraca1, Matthieu Masureel2, Scott A Hollingsworth3

  • 1Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA.

Cell
|December 9, 2020
PubMed
Summary

GPCR phosphorylation patterns, not just the number of phosphates, dictate arrestin binding and conformational changes. This reveals the structural basis for arrestin

Keywords:
all-atom molecular dynamics simulationbiased signalingfunctional selectivitypost-translational modificationprotein–protein interactionsseven-transmembrane receptor

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Area of Science:

  • Biochemistry
  • Cellular Signaling
  • Structural Biology

Background:

  • Arrestin binding to phosphorylated G-protein-coupled receptors (GPCRs) is crucial for cell signaling.
  • The number and arrangement of phosphates on GPCRs influence arrestin-mediated effects.
  • Understanding these phosphorylation patterns is key to deciphering signaling pathways.

Purpose of the Study:

  • To investigate how GPCR phosphorylation patterns influence arrestin binding and conformation.
  • To elucidate the molecular mechanisms underlying these interactions.
  • To provide structural insights into the GPCR-arrestin

Main Methods:

  • Atomic-level molecular simulations.
  • Site-directed spectroscopy.
  • Computational modeling of GPCR-arrestin interactions.

Main Results:

  • GPCR phosphorylation patterns, not just the total number of phosphates, dictate arrestin binding and conformational changes.
  • Different phosphorylation arrangements can lead to distinct arrestin conformations and signaling outcomes.
  • Specific phosphorylation sites exert opposing effects on arrestin behavior.

Conclusions:

  • The arrangement of phosphates on GPCRs acts as a