Assembly of a GPCR-G Protein Complex

Yang Du, Nguyen Minh Duc, Søren G.F. Rasmussen, Daniel Hilger, Xavier Kubiak, Liwen Wang, Jennifer Bohon, Hee Ryung Kim, Marcin Wegrecki, Awuri Asuru, Kyung Min Jeong, Jeongmi Lee, Mark R. Chance, David T. Lodowski, Ka Young Chung

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The activation of G proteins by G protein-coupled receptors (GPCRs) underlies the majority of transmembrane signaling by hormones and neurotransmitters. Recent structures of GPCR-G protein complexes obtained by crystallography and cryoelectron microscopy (cryo-EM) reveal similar interactions between GPCRs and the alpha subunit of different G protein isoforms. While some G protein subtype-specific differences are observed, there is no clear structural explanation for G protein subtype-selectivity. All of these complexes are stabilized in the nucleotide-free state, a condition that does not exist in living cells. In an effort to better understand the structural basis of coupling specificity, we used time-resolved structural mass spectrometry techniques to investigate GPCR-G protein complex formation and G-protein activation. Our results suggest that coupling specificity is determined by one or more transient intermediate states that serve as selectivity filters and precede the formation of the stable nucleotide-free GPCR-G protein complexes observed in crystal and cryo-EM structures. A time-resolved look at how a GPCR engages a G protein reveals intermediates in the process that dictate both specificity for the interaction and the initial steps kicking off downstream signaling.

Original languageEnglish
Pages (from-to)1232-1242
Number of pages11
JournalCell
Volume177
Issue number5
DOIs
Publication statusPublished - 16 May 2019
Externally publishedYes

Keywords

  • conformation
  • dynamics
  • G protein
  • G protein-coupled receptor
  • hydrogen/deuterium exchange mass spectrometry
  • hydroxyl radical footprinting mass spectrometry

Cite this

Du, Y., Duc, N. M., Rasmussen, S. G. F., Hilger, D., Kubiak, X., Wang, L., ... Chung, K. Y. (2019). Assembly of a GPCR-G Protein Complex. Cell, 177(5), 1232-1242. https://doi.org/10.1016/j.cell.2019.04.022
Du, Yang ; Duc, Nguyen Minh ; Rasmussen, Søren G.F. ; Hilger, Daniel ; Kubiak, Xavier ; Wang, Liwen ; Bohon, Jennifer ; Kim, Hee Ryung ; Wegrecki, Marcin ; Asuru, Awuri ; Jeong, Kyung Min ; Lee, Jeongmi ; Chance, Mark R. ; Lodowski, David T. ; Chung, Ka Young. / Assembly of a GPCR-G Protein Complex. In: Cell. 2019 ; Vol. 177, No. 5. pp. 1232-1242.
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author = "Yang Du and Duc, {Nguyen Minh} and Rasmussen, {S{\o}ren G.F.} and Daniel Hilger and Xavier Kubiak and Liwen Wang and Jennifer Bohon and Kim, {Hee Ryung} and Marcin Wegrecki and Awuri Asuru and Jeong, {Kyung Min} and Jeongmi Lee and Chance, {Mark R.} and Lodowski, {David T.} and Chung, {Ka Young}",
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Du, Y, Duc, NM, Rasmussen, SGF, Hilger, D, Kubiak, X, Wang, L, Bohon, J, Kim, HR, Wegrecki, M, Asuru, A, Jeong, KM, Lee, J, Chance, MR, Lodowski, DT & Chung, KY 2019, 'Assembly of a GPCR-G Protein Complex' Cell, vol. 177, no. 5, pp. 1232-1242. https://doi.org/10.1016/j.cell.2019.04.022

Assembly of a GPCR-G Protein Complex. / Du, Yang; Duc, Nguyen Minh; Rasmussen, Søren G.F.; Hilger, Daniel; Kubiak, Xavier; Wang, Liwen; Bohon, Jennifer; Kim, Hee Ryung; Wegrecki, Marcin; Asuru, Awuri; Jeong, Kyung Min; Lee, Jeongmi; Chance, Mark R.; Lodowski, David T.; Chung, Ka Young.

In: Cell, Vol. 177, No. 5, 16.05.2019, p. 1232-1242.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jeong, Kyung Min

AU - Lee, Jeongmi

AU - Chance, Mark R.

AU - Lodowski, David T.

AU - Chung, Ka Young

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Du Y, Duc NM, Rasmussen SGF, Hilger D, Kubiak X, Wang L et al. Assembly of a GPCR-G Protein Complex. Cell. 2019 May 16;177(5):1232-1242. https://doi.org/10.1016/j.cell.2019.04.022