Effect of phosphorylation barcodes on arrestin binding to a chemokine receptor

Qiuyan Chen (), Christopher T. Schafer, Somnath Mukherjee, Kai Wang, Martin Gustavsson, James R. Fuller, Katelyn Tepper, Thomas D. Lamme, Yasmin Aydin, Parth Agrawal, Genki Terashi, Xin-Qiu Yao, Daisuke Kihara, Anthony A. Kossiakoff, Tracy M. Handel () and John J. G. Tesmer ()
Additional contact information
Qiuyan Chen: Indiana University School of Medicine
Christopher T. Schafer: San Diego
Somnath Mukherjee: University of Chicago
Kai Wang: San Diego
Martin Gustavsson: San Diego
James R. Fuller: LLC
Katelyn Tepper: Indiana University School of Medicine
Thomas D. Lamme: Vrije Universiteit Amsterdam
Yasmin Aydin: Indiana University School of Medicine
Parth Agrawal: University of Chicago
Genki Terashi: Purdue University
Xin-Qiu Yao: University of Nebraska Omaha
Daisuke Kihara: Purdue University
Anthony A. Kossiakoff: University of Chicago
Tracy M. Handel: San Diego
John J. G. Tesmer: Purdue University

Nature, 2025, vol. 643, issue 8070, 280-287

Abstract: Abstract Unique phosphorylation ‘barcodes’ installed in different regions of an active seven-transmembrane receptor by different G-protein-coupled receptor (GPCR) kinases (GRKs) have been proposed to promote distinct cellular outcomes1, but it is unclear whether or how arrestins differentially engage these barcodes. Here, to address this, we developed an antigen-binding fragment (Fab7) that recognizes both active arrestin2 (β-arrestin1) and arrestin3 (β-arrestin2) without interacting with bound receptor polypeptides. We used Fab7 to determine the structures of both arrestins in complex with atypical chemokine receptor 3 (ACKR3) phosphorylated in different regions of its C-terminal tail by either GRK2 or GRK5 (ref. 2). The GRK2-phosphorylated ACKR3 resulted in more heterogeneous ‘tail-mode’ assemblies, whereas phosphorylation by GRK5 resulted in more rigid ‘ACKR3-adjacent’ assemblies. Unexpectedly, the finger loops of both arrestins engaged the micelle surface rather than the receptor intracellular pocket, with arrestin3 being more dynamic, partly because of its lack of a membrane-anchoring motif. Thus, both the region of the barcode and the arrestin isoform involved can alter the structure and dynamics of GPCR–arrestin complexes, providing a possible mechanistic basis for unique downstream cellular effects, such as the efficiency of chemokine scavenging and the robustness of arrestin binding in ACKR3.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09024-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:643:y:2025:i:8070:d:10.1038_s41586-025-09024-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09024-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().