Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 26, Pages E3629-E3638Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1604125113
Keywords
GPCR; NMR; SAXS; structure; signaling
Categories
Funding
- Human Frontier Science Program long-term fellowship [LT000297/2011-L]
- Institute for Advanced Study of the Technical University of Munich (TUM-IAS) - German Excellence Initiative
- European Union [291763]
- Center for Integrated Protein Science Munich (CIPSM)
- Helmholtz Center Munich
- National Institutes of Health [GM047467, EB002026]
- Human Frontier Science Program [RGP0060/2016]
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Heterotrimeric G proteins play a pivotal role in the signal-transduction pathways initiated by G-protein-coupled receptor (GPCR) activation. Agonist-receptor binding causes GDP-to-GTP exchange and dissociation of the G alpha subunit from the heterotrimeric G protein, leading to downstream signaling. Here, we studied the internal mobility of a G-protein alpha subunit in its apo and nucleotide-bound forms and characterized their dynamical features at multiple time scales using solution NMR, small-angle X-ray scattering, and molecular dynamics simulations. We find that binding of GTP analogs leads to a rigid and closed arrangement of the G alpha subdomain, whereas the apo and GDP-bound forms are considerably more open and dynamic. Furthermore, we were able to detect two conformational states of the G alpha Ras domain in slow exchange whose populations are regulated by binding to nucleotides and a GPCR. One of these conformational states, the open state, binds to the GPCR; the second conformation, the closed state, shows no interaction with the receptor. Binding to the GPCR stabilizes the open state. This study provides an in-depth analysis of the conformational landscape and the switching function of a G-protein alpha subunit and the influence of a GPCR in that landscape.
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