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Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder-based proteoforms

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Abstract

GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signaling cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defines an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of differently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fine-tuned by various post-translational modifications and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specific partners. In other words, GPCRs and G proteins exist as sets of conformational/basic, inducible/modified, and functioning proteoforms characterized by a broad spectrum of structural features and possessing various functional potentials.

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Acknowledgements

This work was supported in part by the President of the Russian Federation Scholarship SP-3665.2018.4 (A.V.F.), grants from Russian Science Foundation RSCF 18-75-10115 (A.V.F.) and RSCF 19-15-00107 (K.K.T.).

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  1. Alexander V. Fonin and April L. Darling contributed equally to this work.

Authors and Affiliations

  1. Laboratory of structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russian Federation

    Alexander V. Fonin, Irina M. Kuznetsova & Konstantin K. Turoverov

  2. Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    April L. Darling & Vladimir N. Uversky

  3. Department of Biophysics, Peter the Great St. Petersburg Polytechnic University, Polytechnicheskaya av. 29, St. Petersburg, 195251, Russian Federation

    Konstantin K. Turoverov

  4. Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow, Russian Federation

    Vladimir N. Uversky

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Fonin, A.V., Darling, A.L., Kuznetsova, I.M. et al. Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder-based proteoforms. Cell. Mol. Life Sci. 76, 4461–4492 (2019). https://doi.org/10.1007/s00018-019-03276-1

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