{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Perry-Hauser NA"],"funding":["NEI NIH HHS","NIBIB NIH HHS","NIDA NIH HHS","American Heart Association-American Stroke Association","NIGMS NIH HHS","NIH HHS"],"pagination":["167465"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8977243"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["434(7)"],"pubmed_abstract":["Arrestin binding to active phosphorylated G protein-coupled receptors terminates G protein coupling and initiates another wave of signaling. Among the effectors that bind directly to receptor-associated arrestins are extracellular signal-regulated kinases 1/2 (ERK1/2), which promote cellular proliferation and survival. Arrestins may also engage ERK1/2 in isolation in a pre- or post-signaling complex that is likely in equilibrium with the full signal initiation complex. Molecular details of these binary complexes remain unknown. Here, we investigate the molecular mechanisms whereby arrestin-2 and arrestin-3 (a.k.a. β-arrestin1 and β-arrestin2, respectively) engage ERK1/2 in pairwise interactions. We find that purified arrestin-3 binds ERK2 more avidly than arrestin-2. A combination of biophysical techniques and peptide array analysis demonstrates that the molecular basis in this difference of binding strength is that the two non-visual arrestins bind ERK2 via different parts of the molecule. We propose a structural model of the ERK2-arrestin-3 complex in solution using size-exclusion chromatography coupled to small angle X-ray scattering (SEC-SAXS). This binary complex exhibits conformational heterogeneity. We speculate that this drives the equilibrium either toward the full signaling complex with receptor-bound arrestin at the membrane or toward full dissociation in the cytoplasm. As ERK1/2 regulates cell migration, proliferation, and survival, understanding complexes that relate to its activation could be exploited to control cell fate."],"journal":["Journal of molecular biology"],"pubmed_title":["The Two Non-Visual Arrestins Engage ERK2 Differently."],"pmcid":["PMC8977243"],"funding_grant_id":["R01 GM120569","R01 EY011500","16PRE30180007","P41 EB001980","T32 GM008320","S10 OD018090","18PRE34030017","P41 GM103622","R21 DA043680","R35 GM122491","P30 EY008126","R01 GM123252"],"pubmed_authors":["Sharma P","Klug CS","Iverson TM","Zhuo Y","Kaya AI","Vishnivetskiy SA","Dalby KN","Hopkins JB","Schultz KM","Perry-Hauser NA","Zheng C","Perez I","Gurevich VV","Chung KY"],"additional_accession":[]},"is_claimable":false,"name":"The Two Non-Visual Arrestins Engage ERK2 Differently.","description":"Arrestin binding to active phosphorylated G protein-coupled receptors terminates G protein coupling and initiates another wave of signaling. Among the effectors that bind directly to receptor-associated arrestins are extracellular signal-regulated kinases 1/2 (ERK1/2), which promote cellular proliferation and survival. Arrestins may also engage ERK1/2 in isolation in a pre- or post-signaling complex that is likely in equilibrium with the full signal initiation complex. Molecular details of these binary complexes remain unknown. Here, we investigate the molecular mechanisms whereby arrestin-2 and arrestin-3 (a.k.a. β-arrestin1 and β-arrestin2, respectively) engage ERK1/2 in pairwise interactions. We find that purified arrestin-3 binds ERK2 more avidly than arrestin-2. A combination of biophysical techniques and peptide array analysis demonstrates that the molecular basis in this difference of binding strength is that the two non-visual arrestins bind ERK2 via different parts of the molecule. We propose a structural model of the ERK2-arrestin-3 complex in solution using size-exclusion chromatography coupled to small angle X-ray scattering (SEC-SAXS). This binary complex exhibits conformational heterogeneity. We speculate that this drives the equilibrium either toward the full signaling complex with receptor-bound arrestin at the membrane or toward full dissociation in the cytoplasm. As ERK1/2 regulates cell migration, proliferation, and survival, understanding complexes that relate to its activation could be exploited to control cell fate.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2026-05-09T22:22:51.268Z","creation":"2025-02-19T04:46:09.484Z"},"accession":"S-EPMC8977243","cross_references":{"pubmed":["35077767"],"doi":["10.1016/j.jmb.2022.167465"]}}