Pivotal Role of Extended Linker 2 in the Activation of Gα by G Protein-coupled Receptor

Huang, Jian; Sun, Yutong; Zhang, J. Jillian; Huang, Xin

doi:10.1074/jbc.m114.608661

Cited by 9 publications

(8 citation statements)

References 53 publications

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“…The closed and open states of the cleft (the GDP/GTP binding site) are determined by the relative pivoting of the Ras-like domain and the α-helical domain at Linker 2. Given this pivot model, the two domains of Gα could be ‘clam-shell’ opening or ‘rolling-top’ expansion including a relative rotation of the Ras-like domain and the helical domain around an axis through the linkers [29]. In addition to the established role for α5-helix of Gα in connecting GPCRs to the guanine-nucleotide binding pocket, an extended Linker 2 connects GPCRs to the nucleotide binding pocket as well as the α-helical domain of Gα [29].…”

Section: Regulation Of G-proteinsmentioning

confidence: 99%

“…Given this pivot model, the two domains of Gα could be ‘clam-shell’ opening or ‘rolling-top’ expansion including a relative rotation of the Ras-like domain and the helical domain around an axis through the linkers [29]. In addition to the established role for α5-helix of Gα in connecting GPCRs to the guanine-nucleotide binding pocket, an extended Linker 2 connects GPCRs to the nucleotide binding pocket as well as the α-helical domain of Gα [29]. Many more structures in different states and with different GPCRs/G-proteins are needed to fully understand the biochemistry of the G-protein activation cycle.…”

Section: Regulation Of G-proteinsmentioning

confidence: 99%

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Regulation, Signaling, and Physiological Functions of G-Proteins

Syrovatkina

Alegre

Dey

et al. 2016

Journal of Molecular Biology

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381

286

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Heterotrimeric G-proteins mainly relay the information from G-protein-coupled receptors (GPCRs) on the plasma membrane to the inside of cells to regulate various biochemical functions. Depending on the targeted cell types, tissues and organs, these signals modulate diverse physiological functions. The basic schemes of heterotrimeric G-proteins have been outlined. In this review we briefly summarize what is known about the regulation, signaling and physiological functions of G-proteins. We then focus on a few less explored areas such as regulation of G-proteins by non-GPCRs, and the physiological functions of G-proteins that can not be easily explained by the known G-protein signaling pathways. There are new signaling pathways and physiological functions for G-proteins to be discovered and further interrogated. With the advancements in structural and computational biological techniques, we are closer to having a better understanding of how G-proteins are regulated, and the specificity of G-protein interactions with their regulators.

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Section: Regulation Of G-proteinsmentioning

confidence: 99%

Section: Regulation Of G-proteinsmentioning

confidence: 99%

Regulation, Signaling, and Physiological Functions of G-Proteins

Syrovatkina

Alegre

Dey

et al. 2016

Journal of Molecular Biology

Self Cite

381

286

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“…Of note, the labeled residues in switch II expressed increased packing upon receptor coupling which helps to preserve the folding of the nucleotideempty protein. More recently, with mutant screening assay, Huang et al (2015) proposed that GPCR ICL2 directly interacts with β2/β3 loop of Gα to communicate with switch I, which results in opening and closing of α-helical domain and the release of GDP.…”

Section: Conformational Change In the Switch Regions Of Gα Subunitmentioning

confidence: 99%

Structural mechanism of G protein activation by G protein-coupled receptor

Duc

Kim

Chung

2015

European Journal of Pharmacology

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“…G-protein docking simulations using the recently solved crystal structure of the β 1 -AR homodimer suggest that one protomer of the dimer is predominantly responsible for contacting the G-alpha subunit [10]. In an elegant series of experiments using mutant Gs proteins, Huang and colleagues reported a role for the second intracellular loop of the β 2 -AR in G-alpha activation and guanyl nucleotide exchange [48]. Their model, based on the reported crystal structure of the β 2 -AR-G protein complex [35], shows one protomer of a β 2 -AR contacting the G protein alpha subunit, with the TMD1/H8 regions facing inward toward the beta-gamma subunits.…”

Section: Discussionmentioning

confidence: 99%

“…Their model, based on the reported crystal structure of the β 2 -AR-G protein complex [35], shows one protomer of a β 2 -AR contacting the G protein alpha subunit, with the TMD1/H8 regions facing inward toward the beta-gamma subunits. If both protomers of a β 2 -AR homodimer physically associate with the G protein, then these models [35, 48] predict a TMD1/H8 homodimer interface as the TMD4/5 regions appear to be oriented away from the center of the G protein complex. These models are supported by the findings in the present study in which residues in TMD1 and H8 are proposed to play a role in homodimer formation.…”

Section: Discussionmentioning

confidence: 99%

Beta2-adrenergic receptor homodimers: Role of transmembrane domain 1 and helix 8 in dimerization and cell surface expression

Parmar

Grinde

Mazurkiewicz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Even though there are hundreds of reports in the published literature supporting the hypothesis that G protein-coupled receptors (GPCR) form and function as dimers this remains a highly controversial area of research and mechanisms governing homodimer formation are poorly understood. Crystal structures revealing homodimers have been reported for many different GPCR. For adrenergic receptors, a potential dimer interface involving transmembrane domain 1 (TMD1) and helix 8 (H8) was identified in crystal structures of the beta1-adrenergic (β1-AR) and β2-AR. The purpose of this study was to investigate a potential role for TMD1 and H8 in dimerization and plasma membrane expression of functional β2-AR. Charged residues at the base of TMD1 and in the distal portion of H8 were replaced, singly and in combination, with non-polar residues or residues of opposite charge. Wild type and mutant β2-AR, tagged with YFP and expressed in HEK293 cells, were evaluated for plasma membrane expression and function. Homodimer formation was evaluated using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and fluorescence correlation spectroscopy. Amino acid substitutions at the base of TMD1 and in the distal portion of H8 disrupted homodimer formation and caused receptors to be retained in the endoplasmic reticulum. Mutations in the proximal region of H8 did not disrupt dimerization but did interfere with plasma membrane expression. This study provides biophysical evidence linking a potential TMD1/H8 interface with ER export and the expression of functional β2-AR on the plasma membrane.

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Pivotal Role of Extended Linker 2 in the Activation of Gα by G Protein-coupled Receptor

Cited by 9 publications

References 53 publications

Regulation, Signaling, and Physiological Functions of G-Proteins

Regulation, Signaling, and Physiological Functions of G-Proteins

Structural mechanism of G protein activation by G protein-coupled receptor

Beta2-adrenergic receptor homodimers: Role of transmembrane domain 1 and helix 8 in dimerization and cell surface expression

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