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Interaction kinetics between p115-RhoGEF and Gα13 are determined by unique molecular interactions affecting agonist sensitivity
The three RH-RhoGEFs (Guanine nucleotide exchange factors) p115-RhoGEF, LARG (leukemia-associated RhoGEF) and PDZ-RhoGEF link G-protein coupled receptors (GPCRs) with RhoA signaling through activation of Gα12/13. In order to find functional differences in signaling between the different RH-RhoGEFs w...
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| Autoren: | , , |
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| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2022
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| Schlagworte: | |
| Online-Zugang: | PDF-Volltext |
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| Zusammenfassung: | The three RH-RhoGEFs (Guanine nucleotide exchange factors) p115-RhoGEF, LARG (leukemia-associated RhoGEF) and PDZ-RhoGEF link G-protein coupled receptors (GPCRs) with RhoA signaling through activation of Gα12/13. In order to find functional differences in signaling between the different RH-RhoGEFs we examined their interaction with Gα13 in high spatial and temporal resolution, utilizing a FRET-based single cell assay. We found that p115-RhoGEF interacts significantly shorter with Gα13 than LARG and PDZ-RhoGEF, while narrowing the structural basis for these differences down to a single amino acid in the rgRGS domain of p115-RhoGEF. The mutation of this amino acid led to an increased interaction time with Gα13 and an enhanced agonist sensitivity, comparable to LARG, while mutating the corresponding amino acid in Gα13 the same effect could be achieved. While the rgRGS domains of RH-RhoGEFs showed GAP (GTPase-activating protein) activity towards Gα13 in vitro, our approach suggests higher GAP activity of p115-RhoGEF in intact cells. |
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| Beschreibung: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| DOI: | 10.1038/s42003-022-04224-9 |