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Pivotal role of extended linker 2 in the activation of G? by G protein-coupled receptor.


ABSTRACT: G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (G???) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal ?5-helix of G? to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the ?-helical domain of G? during the activation of G? by a GPCR. Here we show that ?-adrenergic receptors activate eight G?s mutant proteins (from a screen of 66 G?s mutants) that are unable to bind G?? subunits in cells. Five of these eight mutants are in the ?F/Linker 2/?2 hinge region (extended Linker 2) that connects the Ras-like GTPase domain and the ?-helical domain of G?s. This extended Linker 2 is the target site of a natural product inhibitor of Gq. Our data show that the extended Linker 2 is critical for G? activation by GPCRs. We propose that a GPCR via its intracellular loop 2 directly interacts with the ?2/?3 loop of G? to communicate to Linker 2, resulting in the opening and closing of the ?-helical domain and the release of GDP during G-protein activation.

SUBMITTER: Huang J 

PROVIDER: S-EPMC4281731 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor.

Huang Jianyun J   Sun Yutong Y   Zhang J Jillian JJ   Huang Xin-Yun XY  

The Journal of biological chemistry 20141120 1


G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (Gαβγ) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal α5-helix of Gα to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the α-helical domain of Gα during the activat  ...[more]

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