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Dimerization/oligomerization in G protein‐coupled receptors (GPCRs) involve the participation of all transmembrane domains
Author(s) -
Sen Saurabh,
Klco Jeffery M,
Hansen Jakob L,
Nikiforovich Gregory V,
Sheikh Soren P,
Baranski Thomas J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a613-a
Subject(s) - g protein coupled receptor , chemistry , transmembrane domain , receptor , biophysics , transmembrane protein , microbiology and biotechnology , biochemistry , biology
Oligomerization of GPCRs is now widely accepted but the mechanism of how GPCRs form larger oligomeric structures is elusive. To comprehensively study the contributions of the lipid‐facing residues of a GPCR to receptor function and oligomerization, we systemically generated chimeric C5a receptors in which five to six lipid‐exposed residues in TM1, TM2, TM4, TM5, TM6 or TM7 were exchanged with the cognate residues from the angiotensin AT1 receptor, another member of GPCR family, which, as shown here, does not form oligomers with the C5a receptor. This novel approach preserved the intrahelical interactions known to stabilize the TM bundle while only altering those residues expected to mediate protein‐protein interactions. Fluorescence micrographs demonstrated that all of the lipid‐facing chimeras were retained in the endoplasmic reticulum; but they are structurally competent enough to bind ligand and activate G proteins. Furthermore, the oligomerization studies revealed a complex set of interactions involving all of the TM helices. We hypothesize that GPCRs constitutively associate into larger oligomers in the ER and that this oligomerization phenomenon is necessary for transport to the plasma membrane. These studies highlight the importance of the lipid‐facing residues in determining the transport competence of GPCRs, outlining a broad molecular signature profile for the oligomerization domain. (NIH).