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Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody

Author

Listed:
  • Mithu Baidya

    (Indian Institute of Technology)

  • Madhu Chaturvedi

    (Indian Institute of Technology)

  • Hemlata Dwivedi-Agnihotri

    (Indian Institute of Technology)

  • Ashutosh Ranjan

    (Indian Institute of Technology)

  • Dominic Devost

    (McGill University)

  • Yoon Namkung

    (McGill University)

  • Tomasz Maciej Stepniewski

    (Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM)
    University of Warsaw)

  • Shubhi Pandey

    (Indian Institute of Technology)

  • Minakshi Baruah

    (Indian Institute of Technology)

  • Bhanupriya Panigrahi

    (Indian Institute of Technology)

  • Parishmita Sarma

    (Indian Institute of Technology)

  • Manish K. Yadav

    (Indian Institute of Technology)

  • Jagannath Maharana

    (Indian Institute of Technology)

  • Ramanuj Banerjee

    (Indian Institute of Technology)

  • Kouki Kawakami

    (Tohoku University)

  • Asuka Inoue

    (Tohoku University)

  • Jana Selent

    (Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM))

  • Stéphane A. Laporte

    (McGill University
    McGill University)

  • Terence E. Hébert

    (McGill University)

  • Arun K. Shukla

    (Indian Institute of Technology)

Abstract

Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs such as the vasopressin receptor subtype 2 (V2R), agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking, which is generally considered to be orchestrated by multiple phosphorylation sites. We have previously shown that mutation of a single phosphorylation site in the V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes despite robust recruitment to the plasma membrane, and compromised ERK1/2 activation. Here, we discover that a synthetic intrabody (Ib30), which selectively recognizes activated βarr1, efficiently rescues the endosomal trafficking of βarr1 and ERK1/2 activation for V2RT360A. Molecular dynamics simulations reveal that Ib30 enriches active-like βarr1 conformation with respect to the inter-domain rotation, and cellular assays demonstrate that it also enhances βarr1-β2-adaptin interaction. Our data provide an experimental framework to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can be potentially integrated in the paradigm of GPCR-targeted drug discovery.

Suggested Citation

  • Mithu Baidya & Madhu Chaturvedi & Hemlata Dwivedi-Agnihotri & Ashutosh Ranjan & Dominic Devost & Yoon Namkung & Tomasz Maciej Stepniewski & Shubhi Pandey & Minakshi Baruah & Bhanupriya Panigrahi & Par, 2022. "Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32386-x
    DOI: 10.1038/s41467-022-32386-x
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    References listed on IDEAS

    as
    1. Qing-Tao He & Peng Xiao & Shen-Ming Huang & Ying-Li Jia & Zhong-Liang Zhu & Jing-Yu Lin & Fan Yang & Xiao-Na Tao & Ru-Jia Zhao & Feng-Yuan Gao & Xiao-Gang Niu & Kun-Hong Xiao & Jiangyun Wang & Changwe, 2021. "Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Naomi R. Latorraca & Jason K. Wang & Brian Bauer & Raphael J. L. Townshend & Scott A. Hollingsworth & Julia E. Olivieri & H. Eric Xu & Martha E. Sommer & Ron O. Dror, 2018. "Molecular mechanism of GPCR-mediated arrestin activation," Nature, Nature, vol. 557(7705), pages 452-456, May.
    3. Punita Kumari & Ashish Srivastava & Ramanuj Banerjee & Eshan Ghosh & Pragya Gupta & Ravi Ranjan & Xin Chen & Bhagyashri Gupta & Charu Gupta & Deepika Jaiman & Arun K. Shukla, 2016. "Functional competence of a partially engaged GPCR–β-arrestin complex," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    4. Roshanak Irannejad & Jin C. Tomshine & Jon R. Tomshine & Michael Chevalier & Jacob P. Mahoney & Jan Steyaert & Søren G. F. Rasmussen & Roger K. Sunahara & Hana El-Samad & Bo Huang & Mark von Zastrow, 2013. "Conformational biosensors reveal GPCR signalling from endosomes," Nature, Nature, vol. 495(7442), pages 534-538, March.
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