Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 34, Pages 14367-14372Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901074106
Keywords
footprinting; mass spectrometry; signal transduction; membrane proteins; radiolysis
Categories
Funding
- National Institutes of Health (NIH) [EY09339, GM079191, EB09998, EB01979, T32EY007157]
- National Institute of Biomedical Imaging and Bioengineering
- Department of Energy
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Structural water molecules may act as prosthetic groups indispensable for proper protein function. In the case of allosteric activation of G protein-coupled receptors (GPCRs), water likely imparts structural plasticity required for agonist-induced signal transmission. Inspection of structures of GPCR superfamily members reveals the presence of conserved embedded water molecules likely important to GPCR function. Coupling radiolytic hydroxyl radical labeling with rapid H2O18 solvent mixing, we observed no exchange of these structural waters with bulk solvent in either ground state or for the Meta II or opsin states. However, the radiolysis approach permitted labeling of selected side chain residues within the transmembrane helices and revealed activation-induced changes in local structural constraints likely mediated by dynamics of both water and protein. These results suggest both a possible general mechanism for water-dependent communication in family A GPCRs based on structural conservation, and a strategy for probing membrane protein structure.
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