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Cellular and Molecular Life Sciences

, Volume 76, Issue 22, pp 4461–4492 | Cite as

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

  • Alexander V. Fonin
  • April L. Darling
  • Irina M. Kuznetsova
  • Konstantin K. Turoverov
  • Vladimir N. UverskyEmail author
Review

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.

Keywords

G proteins G protein-coupled receptors Intrinsically disordered protein Proteoform Protein–protein interaction Post-translational modification Alternative splicing 

Notes

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.).

Supplementary material

18_2019_3276_MOESM1_ESM.pdf (18 mb)
Supplementary material 1 (PDF 18461 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Laboratory of structural Dynamics, Stability and Folding of Proteins, Institute of CytologyRussian Academy of SciencesSt. PetersburgRussian Federation
  2. 2.Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of MedicineUniversity of South FloridaTampaUSA
  3. 3.Department of BiophysicsPeter the Great St. Petersburg Polytechnic UniversitySt. PetersburgRussian Federation
  4. 4.Institute for Biological InstrumentationRussian Academy of SciencesMoscowRussian Federation

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