Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses

Yuki Toyama, Hanaho Kano, Yoko Mase, Mariko Yokogawa, Masanori Osawa and Ichio Shimada ()
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Yuki Toyama: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Hanaho Kano: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Yoko Mase: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Mariko Yokogawa: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Masanori Osawa: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Ichio Shimada: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Heterotrimeric guanine-nucleotide-binding proteins (G proteins) serve as molecular switches in signalling pathways, by coupling the activation of cell surface receptors to intracellular responses. Mutations in the G protein α-subunit (Gα) that accelerate guanosine diphosphate (GDP) dissociation cause hyperactivation of the downstream effector proteins, leading to oncogenesis. However, the structural mechanism of the accelerated GDP dissociation has remained unclear. Here, we use magnetic field-dependent nuclear magnetic resonance relaxation analyses to investigate the structural and dynamic properties of GDP bound Gα on a microsecond timescale. We show that Gα rapidly exchanges between a ground-state conformation, which tightly binds to GDP and an excited conformation with reduced GDP affinity. The oncogenic D150N mutation accelerates GDP dissociation by shifting the equilibrium towards the excited conformation.

Date: 2017
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DOI: 10.1038/ncomms14523

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