IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32386-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32386-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-32386-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dylan Scott Eiger & Noelia Boldizsar & Christopher Cole Honeycutt & Julia Gardner & Stephen Kirchner & Chloe Hicks & Issac Choi & Uyen Pham & Kevin Zheng & Anmol Warman & Jeffrey S. Smith & Jennifer Y, 2022. "Location bias contributes to functionally selective responses of biased CXCR3 agonists," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Harrison M. York & Kunaal Joshi & Charles S. Wright & Laura Z. Kreplin & Samuel J. Rodgers & Ullhas K. Moorthi & Hetvi Gandhi & Abhishek Patil & Christina A. Mitchell & Srividya Iyer-Biswas & Senthil , 2023. "Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Shane C. Wright & Aikaterini Motso & Stefania Koutsilieri & Christian M. Beusch & Pierre Sabatier & Alessandro Berghella & Élodie Blondel-Tepaz & Kimberley Mangenot & Ioannis Pittarokoilis & Despoina-, 2023. "GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Ruibo Zhai & Zhuoqi Wang & Zhaofei Chai & Xiaogang Niu & Conggang Li & Changwen Jin & Yunfei Hu, 2023. "Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Parishmita Sarma & Carlo Marion C. Carino & Deeksha Seetharama & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Xue Rui & Yubo Cao & Kouki Kawakami & Poonam Kumari & Yu-Chih Chen & Kathryn E. Luker & Pre, 2023. "Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Raphael S. Haider & Edda S. F. Matthees & Julia Drube & Mona Reichel & Ulrike Zabel & Asuka Inoue & Andy Chevigné & Cornelius Krasel & Xavier Deupi & Carsten Hoffmann, 2022. "β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Baptiste Fischer & Tomasz Uchański & Aidana Sheryazdanova & Simon Gonzalez & Alexander N. Volkov & Elke Brosens & Thomas Zögg & Valentina Kalichuk & Steven Ballet & Wim Versées & Anna A. Sablina & Els, 2024. "Allosteric nanobodies to study the interactions between SOS1 and RAS," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    9. Amal El Daibani & Joseph M. Paggi & Kuglae Kim & Yianni D. Laloudakis & Petr Popov & Sarah M. Bernhard & Brian E. Krumm & Reid H. J. Olsen & Jeffrey Diberto & F. Ivy Carroll & Vsevolod Katritch & Bern, 2023. "Molecular mechanism of biased signaling at the kappa opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Alexei Sirbu & Marc Bathe-Peters & Jothi L. M. Kumar & Asuka Inoue & Martin J. Lohse & Paolo Annibale, 2024. "Cell swelling enhances ligand-driven β-adrenergic signaling," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32386-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.