Fast-diffusing receptor collisions with slow-diffusing peptide ligand assemble the ternary parathyroid hormone–GPCR–arrestin complex

Jonathan Pacheco, Karina A. Peña, Sofya Savransky, Alexandre Gidon, Gerald R. V. Hammond, John Janetzko and Jean-Pierre Vilardaga ()
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Jonathan Pacheco: University of Pittsburgh School of Medicine
Karina A. Peña: University of Pittsburgh School of Medicine
Sofya Savransky: University of Pittsburgh School of Medicine
Alexandre Gidon: University of Pittsburgh School of Medicine
Gerald R. V. Hammond: University of Pittsburgh School of Medicine
John Janetzko: Stanford University School of Medicine
Jean-Pierre Vilardaga: University of Pittsburgh School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The assembly of a peptide ligand, its receptor, and β-arrestin (βarr) into a ternary complex within the cell membrane is a crucial aspect of G protein-coupled receptor (GPCR) signaling. We explore this assembly by attaching fluorescent moieties to the parathyroid hormone (PTH) type 1 receptor (PTH1R), using PTH as a prototypical peptide hormone, along with βarr and clathrin, and recording dual-color single-molecule imaging at the plasma membrane of live cells. Here we show that PTH1R exhibits a near-Brownian diffusion, whereas unbound hormone displays limited mobility and slow lateral diffusion at the cell surface. The formation of the PTH–PTH1R–βarr complex occurs in three sequential steps: (1) receptor and ligand collisions, (2) phosphoinositide (PIP3)-dependent recruitment and conformational change of βarr molecules at the plasma membrane, and (3) collision of most βarr molecules with the ligand-bound receptor within clathrin clusters. Our results elucidate the non-random pathway by which PTH–PTH1R–βarr complex is formed and unveil the critical role of PIP3 in regulating GPCR signaling.

Date: 2024
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DOI: 10.1038/s41467-024-54772-3

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