Simulating G Protein-Coupled Receptors in Native-Like Membranes: From Monomers to Oligomers - Methods in Cell Biology - page 77

membrane-protein boundary based on different protein conformations induced by
ligand. In addition, the authors describe how each system displays particular residual
mismatch landscapes as a result of these different deformation patterns. It was con-
cluded that the segments of the 5-HT 2A receptor with the largest drive for mismatch-
driven oligomerization were TM5 in the 5HT-bound configuration, TM4 and TM5 in
the LSD-bound configuration, and TM1 in the KET-bound configuration. In addi-
tion, the authors postulate potential dimerization interfaces for this receptor that
go along with scientific data and previously reported data for other GPCR systems
( Fotiadis et al., 2006, 2003; Guo, Shi, Filizola, Weinstein, & Javitch, 2005; Mancia,
Assur, Herman, Siegel, & Hendrickson, 2008 ).
Therefore, the hydrophobic mismatch between receptor and membrane is being
suggested to be a regulatory factor used by nature to modulate GPCR functioning. It
seems that one way for the GPCR-membrane system to minimize this energetic
penalty in nature is forming higher-order GPCR complexes that allow matching
the unfavorable exposed receptor region and burying them in the newly formed re-
ceptor-receptor interface. Hence, the residual hydrophobic mismatch might be an
important driving factor to facilitate receptor oligomerization, an issue of high rel-
evance for fine-tuning GPCR signaling. Computational approaches to study GPCR
oligomerization are described in the next section.
4.3 GPCR DIMERS AND OLIGOMERS IN MEMBRANES
4.3.1 Modeling GPCR-GPCR interactions
The interaction between GPCRs has been largely controversial mainly because the
GPCR architecture allows certain monomers to signal individually ( Whorton et al.,
2007 ). Today, we know that an altered communication between GPCR monomers
can influence the regulation of important diseases such as schizophrenia or Parkin-
son's disease ( Guix`-Gonz´lez et al., 2012 ). Thus, while the functional communica-
tion between GPCRs is a fact, only during the last decade have scientists searched for
a potential physical interaction between GPCR monomers that confirms the exis-
tence of GPCR heteromers. Various biochemical and biophysical techniques have
greatly enriched the information we currently hold on GPCR-GPCR interactions
and have helped in defining specific GPCR dimers and oligomers ( Kaczor &
Selent, 2011 ). GPCRs, as many other membrane receptors, seem to form dimers
and higher-order oligomers in cells ( Han, Moreira, Urizar, Weinstein, & Javitch,
2009; Milligan, 2009 ). The first crystal of a mammalian GPCR could not come to
light until 2000, when Palczewski et al. (2000) determined the structure of bovine
rhodopsin. Thereafter, an interesting series of class A GPCR crystals have been
solved, including a b 2 -adrenergic receptor bound to a G protein heterotrimer
( Rasmussen et al., 2011 ). However, only a few of these crystals help in understanding
the nature of GPCR oligomers ( Sadiq et al., 2013 ); among them, the first crystal
structure of an adrenoceptor homomer has been very recently solved ( Huang,