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{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T12:49:42Z","timestamp":1702212582598},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T00:00:00Z","timestamp":1681084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS028471"]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The \u03b2<jats:sub>2<\/jats:sub>adrenergic receptor\u2019s (\u03b2<jats:sub>2<\/jats:sub>AR) 71 amino acid CT is a substrate for GPCR kinases and binds \u03b2-arrestins to regulate signaling. Here we show that the \u03b2<jats:sub>2<\/jats:sub>AR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking \u03b2-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged \u03b2<jats:sub>2<\/jats:sub>AR-CT serves as an autoinhibitory factor via interacting with the positively charged cytoplasmic surface of the receptor to limit access to G-proteins. The stability of this interaction is influenced by agonists and allosteric modulators, emphasizing that the CT plays important role in allosterically regulating GPCR activation.<\/jats:p>","DOI":"10.1038\/s41467-023-37233-1","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T09:03:20Z","timestamp":1681117400000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Function and dynamics of the intrinsically disordered carboxyl terminus of \u03b22 adrenergic receptor"],"prefix":"10.1038","volume":"14","author":[{"given":"Jie","family":"Heng","sequence":"first","affiliation":[]},{"given":"Yunfei","family":"Hu","sequence":"additional","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0002-9287-8704","authenticated-orcid":false,"given":"Guillermo","family":"P\u00e9rez-Hern\u00e1ndez","sequence":"additional","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0003-0805-4049","authenticated-orcid":false,"given":"Asuka","family":"Inoue","sequence":"additional","affiliation":[]},{"given":"Jiawei","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Xiuyan","family":"Ma","sequence":"additional","affiliation":[]},{"given":"Xiaoou","family":"Sun","sequence":"additional","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0002-2507-8619","authenticated-orcid":false,"given":"Kouki","family":"Kawakami","sequence":"additional","affiliation":[]},{"ORCID":"http:\/\/orcid.org\/0000-0002-8597-0609","authenticated-orcid":false,"given":"Tatsuya","family":"Ikuta","sequence":"additional","affiliation":[]},{"given":"Jienv","family":"Ding","sequence":"additional","affiliation":[]},{"given":"Yujie","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Lujia","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Sijia","family":"Peng","sequence":"additional","affiliation":[]},{"given":"Xiaogang","family":"Niu","sequence":"additional","affiliation":[]},{"given":"Hongwei","family":"Li","sequence":"additional","affili
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