Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 27, Pages 24299-24305Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M202743200
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Funding
- NHLBI NIH HHS [R01 HL064845, HL57470, R01 HL057470] Funding Source: Medline
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A key step in transmembrane (TM) signal transduction by G-protein-coupled receptors (GPCRs) is the ligand-induced conformational change of the receptor, which triggers the activation of a guanine nucleotide-binding protein. GPCRs contain a seven-TM helical structure essential for signal transduction in response to a large variety of sensory and hormonal signals. Primary structure comparison of GPCRs has shown that the second TM helix contains a highly conserved Asp residue, which is critical for agonist activation in these receptors. How conformational changes in TM2 relate to signal transduction by a GPCR is not known, because activation-induced conformational changes in TM2 helix have not been measured. Here we use modification of reporter cysteines to measure water accessibility at specific residues in TM2 of the type I receptor for the octapeptide hormone angiotensin II. Activation-dependent changes in the accessibility of Cys(76) on TM2 were measured in constitutively activated mutants. These changes were directly correlated with measurement of function, establishing the link between physical changes in TM2 and function. Accessibility changes were measured at several consecutive residues on TM2, which suggest that TM2 undergoes a transmembrane movement in response to activation. This is the first report of in situ measurement of TAU movement in a GPCR.
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