IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-28789-5.html
   My bibliography  Save this article

Kinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling

Author

Listed:
  • Kelly J. Culhane

    (Cell Biology and Development, University of Minnesota)

  • Tejas M. Gupte

    (Cell Biology and Development, University of Minnesota)

  • Indrani Madhugiri

    (Chemical Engineering Division, CSIR-National Chemical Laboratory)

  • Chetan J. Gadgil

    (Chemical Engineering Division, CSIR-National Chemical Laboratory
    CSIR-Institute of Genomics and Integrative Biology)

  • Sivaraj Sivaramakrishnan

    (Cell Biology and Development, University of Minnesota)

Abstract

Established models of ternary complex formation between hormone, G protein coupled receptor (GPCR), and G protein assume that all interactions occur under equilibrium conditions. However, recent studies have established that the lifetimes of these interactions are comparable to the duration of hormone activated GPCR signaling. To simulate interactions during such non-equilibrium conditions, we propose a kinetic model wherein the receptor undergoes rate-limiting transitions between two hormone-bound active states. Simulations, using experimentally measured parameters, demonstrate transient states in ternary complex formation, and delineate the phenomenon of GPCR priming, wherein non-cognate G proteins substantially enhance cognate G protein signaling. Our model reveals that kinetic barriers of slow receptor interconversion can be overcome through allokairic modulation, a regulatory mechanism of ternary complex formation and downstream signaling.

Suggested Citation

  • Kelly J. Culhane & Tejas M. Gupte & Indrani Madhugiri & Chetan J. Gadgil & Sivaraj Sivaramakrishnan, 2022. "Kinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28789-5
    DOI: 10.1038/s41467-022-28789-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-28789-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-28789-5?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. Brian T. DeVree & Jacob P. Mahoney & Gisselle A. Vélez-Ruiz & Soren G. F. Rasmussen & Adam J. Kuszak & Elin Edwald & Juan-Jose Fung & Aashish Manglik & Matthieu Masureel & Yang Du & Rachel A. Matt & E, 2016. "Allosteric coupling from G protein to the agonist-binding pocket in GPCRs," Nature, Nature, vol. 535(7610), pages 182-186, July.
    2. Tejas M. Gupte & Michael Ritt & Matthew Dysthe & Rabia U. Malik & Sivaraj Sivaramakrishnan, 2019. "Minute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    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. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Anastasiia Gusach & Yang Lee & Armin Nikpour Khoshgrudi & Elizaveta Mukhaleva & Ning Ma & Eline J. Koers & Qingchao Chen & Patricia C. Edwards & Fanglu Huang & Jonathan Kim & Filippo Mancia & Dmitry B, 2024. "Molecular recognition of an odorant by the murine trace amine-associated receptor TAAR7f," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Kazem Asadollahi & Sunnia Rajput & Lazarus Andrew Zhang & Ching-Seng Ang & Shuai Nie & Nicholas A. Williamson & Michael D. W. Griffin & Ross A. D. Bathgate & Daniel J. Scott & Thomas R. Weikl & Guy N., 2023. "Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Xinyu Xu & Jeremy Shonberg & Jonas Kaindl & Mary J. Clark & Anne Stößel & Luis Maul & Daniel Mayer & Harald Hübner & Kunio Hirata & A. J. Venkatakrishnan & Ron O. Dror & Brian K. Kobilka & Roger K. Su, 2023. "Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Kevin M. Knight & Brian E. Krumm & Nicholas J. Kapolka & W. Grant Ludlam & Meng Cui & Sepehr Mani & Iya Prytkova & Elizabeth G. Obarow & Tyler J. Lefevre & Wenyuan Wei & Ning Ma & Xi-Ping Huang & Jona, 2024. "A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, 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_s41467-022-28789-5. 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.