Dimerization in GPCR mobility and signaling

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Many types of cell surface as well as intracellular DNA-binding receptors exist and function as dimers; formation of homodimers or heterodimers appears to not only provide molecular mechanisms for agonist-induced activation but also increase specificity of ligand recognition and versatility of downstream signaling. G-protein-coupled receptors (GPCRs) were long thought to be an exception, but in recent years a lot of evidence has accumulated that GPCRs also can form dimers, even though it is far from certain when and where they actually do so under physiological conditions. Dimerization of GPCRs does not generally seem to be required for ligand recognition or signaling. However, dimerization may serve to affect receptor mobility at the cell surface and in intracellular trafficking, and may be involved in and affect their signaling functions.

Introduction

Most receptors exist and function as dimers  this is true for cytosolic/nuclear DNA-binding receptors as well as for many families of cell surface receptors [1, 2]. Dimerization can occur between identical (homodimerization) or different (heterodimerization) proteins, and both processes have been observed for receptors. There are many ways in which dimers can be formed. Interactions with entirely different types of proteins have been observed and dimerization may occur with just one or with a variety of partners, leading to a multitude of receptor homomers and heteromers as well as to homomeric and heteromeric receptor complexes [3].

Why would a receptor ‘want’ to dimerize? It appears that dimerization allows the receptor to acquire a number of properties that a monomer does not have. Some of these are listed in Table 1. For example, both protomers within a dimeric complex can contribute to the binding site for the ligand, and thus the nature of the second protomer can determine ligand specificity of a receptor in a dimer. A prominent case for this are the receptors for transforming growth factor (TGF) superfamily members, which are composed of two classes of serine/threonine kinase receptors, termed type I and type II. The seven type I and five type II receptors together with the many ligands generate a plethora of distinct ligand/receptor complexes [4].

Moreover, many cell surface receptors have a single membrane spanning domain, and it is difficult to see how this can transduce a signal across the membrane; however, in a dimer the two moieties can change their relative distance or orientation and thus extracellular ligand binding can change intracellular properties of a dimeric receptor. This is the case for many receptor tyrosine kinases that can often be activated not only by their (monomeric or dimeric) ligands, but also by antibodies that cross-bridge two receptor monomers [5].

And third, an interaction of the intracellular parts of the two protomers may provide an activation mechanism, as in the case of tyrosine kinase receptors where the intracellular tyrosine kinase moiety of one protomer phosphorylates the intracellular part of the other protomer, which can lead to enhanced activity of the tyrosine kinases and to the creation of phosphotyrosines as docking sites for signaling proteins [6].

G-protein-coupled receptors have classically been perceived as receptors that do not ‘need’ to dimerize [1]: their heptahelical structure allows plenty of movements and rearrangements that permit a transfer of the activation signal across the cell membrane, and in fact such agonist-induced structural alterations have begun to be elucidated both in structural and in kinetic terms [7, 8, 9, 10, 11]. The tightly packed structure would also assure ligand specificity, and the docking of G-proteins to the intracellular face of receptors in their activated form provided a suitable transduction mechanism.

And in fact, recent data have confirmed that monomeric signaling of GPCRs is possible and occurs with physiological speed: single (i.e. monomeric) β2-adrenergic receptors as well as rhodopsin and μ-opioid receptors in small lipid vesicles have been shown to couple to their respective G-proteins [12••, 13, 14], and monomeric rhodopsin in solution has been shown to activate its G-protein transducin at the diffusion limit [15]. These experiments indicate that indeed GPCRs do not need to dimerize in order to execute their basic function of transducing a signal from ligand binding to G-protein activation.

Section snippets

Evidence for GPCR dimerization

However, during the last two decades, an increasing number of observations have indicated that dimer and presumably higher order oligomer formation occurs in GPCRs. These observations are reviewed in more detail elsewhere in this volume [16]. Early findings have been reviewed in depth by Hébert and Bouvier [17]; they included functional complementation of dysfunctional receptors, coprecipitation of differently tagged GPCRs, dimer visualization in SDS-polyacrylamide gels and their disruption by

GPCR mobility and assembly

Most early data on GPCR dimers suggested that dimerization of GPCRs occurred early on in the biosynthetic pathway [31]. This was evident, for example, in the case of the GABAB-receptor just mentioned, where the interaction of the C-termini of the B1-subunit and the B2-subunit is required for cell surface targeting, and also from studies of mutants of the V2-vasopressin receptor that cause diabetes insipidus and are retained already as dimers in the endoplasmatic reticulum [32]. This would

Signaling in GPCR dimers

GPCR dimerization and oligomerization have been mostly studied in terms of assembly and intracellular trafficking. A much less studied question concerns the effects that dimerization may have on receptor signaling. The most conclusive evidence in this field comes, again, from the GABAB-receptor. As noted above, this receptor functions only as a heterodimer, where the B1-protomer is responsible for ligand binding and the B2-protomer for G-protein coupling and signaling. This indicates two major

Conclusion and future perspectives

Although GPCRs can in many cases function as monomers, they often appear to assemble into dimers, and in some cases even tetramers and higher order complexes. Dimer assembly may occur during biosynthesis, as is certainly the case for receptors that only reach the cell surface in a dimeric form. But GPCR assemblies may also be more transient and dynamic  presumably just as a consequence of various affinities that the protomers in such an assembly may have for each other. The regulation and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Research in the author's laboratory is supported by an Advanced Investigator Grant of the European Research Council, by grants from the Deutsche Forschungsgemeinschaft (SFB487 and 688), and by a grant of the Fondation Leducq. The sponsors had no involvement in study design, collection, analysis, and interpretation of data, writing or in the decision to submit the paper for publication. The contributions of former and present coworkers to the research discussed in this review are gratefully

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