Structural basis of G protein-coupled receptor function
Section snippets
Diversity of ligand recognition and signal transduction
A fine-tuned communication between individual cells is an essential prerequisite for the coordinated functioning of a multicellular organism. Cells have the ability to process vast amounts of information conveyed to them by extracellular signals (such as hormones, neurotransmitters, autacoids, growth factors, and odorants) and by physical signals (such as light). Most of these signals do not enter the cell, but affect membranous receptors which depend on heterotrimeric guanine
Folding, assembly and oligomerization of GPCRs
Integral membrane proteins like GPCRs are partially buried in the non-polar environment of the lipid bilayer. The correct integration and orientation is guided by a complex translocation machinery residing in the endoplasmatic reticulum (ER) (Rapoport et al., 1996). Following an initial translocation of the N-terminal receptor portion into the ER lumen, the folding procedure takes place in two distinguishable stages. In stage I, hydrophobic α-helices are established across the lipid bilayer,
Current models of receptor activation
The classical ternary complex model of receptor action had to be extended in order to account for the fact that many receptors can activate G proteins in absence of agonist (Lefkowitz et al., 1993). Based on these seminal observations, receptors are assumed to exist in an equilibrium between the inactive state R and the active state R*. The model predicts that even in the absence of agonist, a certain fraction of receptors will spontaneously adopt an active conformation, permitting
Structural basis of receptor/G protein coupling specificity
In most cases, interaction of a given receptor with a distinct G protein is governed by a high degree of selectivity, and only a limited set of G proteins are recognized by an activated receptor. Numerous in vitro mutagenesis studies have been performed in order to understand how coupling selectivity is achieved (Conklin et al., 1993, Liu et al., 1995b, Kostenis et al., 1997, Kostenis et al., 1998, Wess, 1998). Studies highlighting an interaction of distinct α subunits with peptides derived
Acknowledgements
We would like to thank Klaus-Peter Hofmann, Berlin, and Uwe Rudolph and Hanns Möhler, Zürich, for helpful discussions. We are grateful to Jürgen Wess, Bethesda, MD, for making manuscripts available to us prior to publication. The authors’ own work discussed in this article was supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie.
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