Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor

Jie Heng, Yunfei Hu, Guillermo Pérez-Hernández, Asuka Inoue, Jiawei Zhao, Xiuyan Ma, Xiaoou Sun, Kouki Kawakami, Tatsuya Ikuta, Jienv Ding, Yujie Yang, Lujia Zhang, Sijia Peng, Xiaogang Niu, Hongwei Li, Ramon Guixà-González, Changwen Jin, Peter W. Hildebrand, Chunlai Chen () and Brian K. Kobilka ()
Additional contact information
Jie Heng: Tsinghua University
Yunfei Hu: Peking University
Guillermo Pérez-Hernández: Institute of Medical Physics and Biophysics
Asuka Inoue: Tohoku University
Jiawei Zhao: Tsinghua University
Xiuyan Ma: Tsinghua University
Xiaoou Sun: Tsinghua University
Kouki Kawakami: Tohoku University
Tatsuya Ikuta: Tohoku University
Jienv Ding: Peking University
Yujie Yang: Peking University
Lujia Zhang: Tsinghua University
Sijia Peng: Tsinghua University
Xiaogang Niu: Peking University
Hongwei Li: Peking University
Ramon Guixà-González: Paul Scherrer Institute
Changwen Jin: Peking University
Peter W. Hildebrand: Institute of Medical Physics and Biophysics
Chunlai Chen: Tsinghua University
Brian K. Kobilka: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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 β2 adrenergic receptor’s (β2AR) 71 amino acid CT is a substrate for GPCR kinases and binds β-arrestins to regulate signaling. Here we show that the β2AR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking β-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged β2AR-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.

Date: 2023
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DOI: 10.1038/s41467-023-37233-1

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