Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 23, Pages 9420-9424Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105810108
Keywords
signal transduction; structural polymorphism
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Funding
- National Institutes of Health [GM080403, EY006062, EY005216]
- National Research Service Award [MH086222]
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In G-protein signaling, an activated receptor catalyzes GDP/GTP exchange on the G(alpha) subunit of a heterotrimeric G protein. In an initial step, receptor interaction with G(alpha) acts to allosterically trigger GDP release from a binding site located between the nucleotide binding domain and a helical domain, but the molecular mechanism is unknown. In this study, site-directed spin labeling and double electron-electron resonance spectroscopy are employed to reveal a large-scale separation of the domains that provides a direct pathway for nucleotide escape. Cross-linking studies show that the domain separation is required for receptor enhancement of nucleotide exchange rates. The interdomain opening is coupled to receptor binding via the C-terminal helix of G(alpha), the extension of which is a high-affinity receptor binding element.
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