GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner
Abstract Responses from G protein-coupled receptors (GPCRs) are downregulated in a precisely orchestrated process called desensitization. This process consists of two major steps: phosphorylation of the receptor by GPCR kinases (GRKs), predominantly on its C-terminus, and recruitment of arrestin, re...
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Nature Portfolio
2025-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08301-7 |
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| author | Arnelle Löbbert Nils Lorz Edda S. F. Matthees Philip Rößler Carsten Hoffmann Alvar D. Gossert |
| author_facet | Arnelle Löbbert Nils Lorz Edda S. F. Matthees Philip Rößler Carsten Hoffmann Alvar D. Gossert |
| author_sort | Arnelle Löbbert |
| collection | DOAJ |
| description | Abstract Responses from G protein-coupled receptors (GPCRs) are downregulated in a precisely orchestrated process called desensitization. This process consists of two major steps: phosphorylation of the receptor by GPCR kinases (GRKs), predominantly on its C-terminus, and recruitment of arrestin, resulting in different signaling outcomes. Yet, it remains unclear how the phosphorylation pattern on the receptor is determined. We carried out an NMR-based study of the phosphorylation patterns generated by GRK1 and GRK2 on C-terminal peptides of selected receptors (rhodopsin for GRK1, and β1- and β2-adrenergic receptors (ARs) for GRK2). Our data reveal that the kinases are promiscuous with respect to the substrate peptide, but produce clearly defined phosphorylation patterns on each substrate. We found pronounced differences in the rates at which certain residues are phosphorylated, in particular in the PXPP motifs in rhodopsin and β1AR. These results show that GRKs produce well-defined phosphorylation patterns in absence of further modulators like the full receptor or Gβγ, and that the time profile of the phosphorylation barcode seems to be largely encoded in the minimal pair of C-terminal peptide and GRK. The data further suggest that arrestin might encounter different phosphorylation barcodes over time, hinting at the possibility of time-dependent arrestin responses. |
| format | Article |
| id | doaj-art-2a7a6c21d8bd49ebb69d25bf9abf64a6 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-2a7a6c21d8bd49ebb69d25bf9abf64a62025-08-20T03:21:03ZengNature PortfolioCommunications Biology2399-36422025-06-018111210.1038/s42003-025-08301-7GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical mannerArnelle Löbbert0Nils Lorz1Edda S. F. Matthees2Philip Rößler3Carsten Hoffmann4Alvar D. Gossert5Institute of Biochemistry, Department of Biology, ETH ZürichInstitute of Biochemistry, Department of Biology, ETH ZürichInstitute of Molecular Cell Biology, University Hospital Jena, Friedrich Schiller UniversityInstitute of Biochemistry, Department of Biology, ETH ZürichInstitute of Molecular Cell Biology, University Hospital Jena, Friedrich Schiller UniversityInstitute of Biochemistry, Department of Biology, ETH ZürichAbstract Responses from G protein-coupled receptors (GPCRs) are downregulated in a precisely orchestrated process called desensitization. This process consists of two major steps: phosphorylation of the receptor by GPCR kinases (GRKs), predominantly on its C-terminus, and recruitment of arrestin, resulting in different signaling outcomes. Yet, it remains unclear how the phosphorylation pattern on the receptor is determined. We carried out an NMR-based study of the phosphorylation patterns generated by GRK1 and GRK2 on C-terminal peptides of selected receptors (rhodopsin for GRK1, and β1- and β2-adrenergic receptors (ARs) for GRK2). Our data reveal that the kinases are promiscuous with respect to the substrate peptide, but produce clearly defined phosphorylation patterns on each substrate. We found pronounced differences in the rates at which certain residues are phosphorylated, in particular in the PXPP motifs in rhodopsin and β1AR. These results show that GRKs produce well-defined phosphorylation patterns in absence of further modulators like the full receptor or Gβγ, and that the time profile of the phosphorylation barcode seems to be largely encoded in the minimal pair of C-terminal peptide and GRK. The data further suggest that arrestin might encounter different phosphorylation barcodes over time, hinting at the possibility of time-dependent arrestin responses.https://doi.org/10.1038/s42003-025-08301-7 |
| spellingShingle | Arnelle Löbbert Nils Lorz Edda S. F. Matthees Philip Rößler Carsten Hoffmann Alvar D. Gossert GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner Communications Biology |
| title | GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner |
| title_full | GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner |
| title_fullStr | GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner |
| title_full_unstemmed | GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner |
| title_short | GPCR kinases phosphorylate GPCR C-terminal peptides in a hierarchical manner |
| title_sort | gpcr kinases phosphorylate gpcr c terminal peptides in a hierarchical manner |
| url | https://doi.org/10.1038/s42003-025-08301-7 |
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