| Autor: |
Cao, Yubo, van der Velden, Wijnand J. C., Namkung, Yoon, Nivedha, Anita K., Cho, Aaron, Sedki, Dana, Holleran, Brian, Lee, Nicholas, Leduc, Richard, Muk, Sanychen, Le, Keith, Bhattacharya, Supriyo, Vaidehi, Nagarajan, Laporte, Stéphane A. |
| Předmět: |
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| Zdroj: |
Science Signaling; 8/8/2023, Vol. 16 Issue 797, p1-15, 15p |
| Abstrakt: |
G protein–coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gαq and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gαq coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation. Residue stretches in transmembrane domain 4 conferred β-arrestin bias and represented an important structural element in AT1R for functional selectivity. Furthermore, we identified allosteric small-molecule binding sites that were enclosed by communities of residues that produced biased signaling when mutated. Last, we showed that allosteric communication within AT1R emanating from the Gαq coupling site spread beyond the orthosteric AngII-binding site and across different regions of the receptor, including currently unresolved structural regions. Our findings reveal structural elements and mechanisms within AT1R that bias Gαq and β-arrestin coupling and that could be harnessed to design biased receptors for research purposes and to develop allosteric modulators. Editor's summary: The angiotensin II type 1 receptor (AT1R) exerts distinct biological effects depending on whether it couples to the G protein Gαq or the scaffolding protein β-arrestin. To identify residues that allosterically regulated effector coupling, Cao et al. characterized 359 alanine or glycine substitution mutants of AT1R. Those that affected Gαq coupling occurred throughout the receptor in multiple structural regions and were greater in number than those that modulated β-arrestin coupling, which were concentrated in transmembrane domain 4. Many residues were distal to the ligand-binding site. Moreover, AT1R contained multiple allosteric communication pathways, suggesting the possibility of identifying additional sites to allosterically modulate signaling downstream of AT1R activation. –Wei Wong [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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