Oligomerization of GPCRs

The recent explosion of number of papers on GPCR dimerization is summarized in several reviews.81112 This chapter is devoted to briefly show importance of oligomerization of GPCRs, current state of knowledge in this area and potential applications. 

Extracellular, transmembrane (TM), and/or C-terminal regions have been suggested to be involved in the oligomerization process of GPCRs. 

The Prediction of Likely Interfaces of Oligomerization Between TM Regions of GPCRs... 

The earlier computational studies (151,152,175,184,185) considered both domain-swapped and contact dimers as equally possible mechanisms of GPCR oligomerization. In contrast, the later computational studies on GPCR oligomerization (186-189) take into account only the hypothesis of contact dimers, supported by the more recent experimental evidence. For the prediction of heterodimer interfaces, the recent studies use a modified CMA methodology, termed subtractive correlated mutation (SCM) analysis (187,188). A similar method for the identification of physically interacting protein pairs has recently been reported in the literature (180). 

Modeling may provide valuable information about interfaces of interacting proteins and how oligomeric state of GPCRs affects binding of other proteins. This is especially attractive taking into account that direct proof of the structure of complexes involving membrane proteins is very difficult via crystallization or NMR measurements. 

The reported data predate the observation of GPCR oligomerization, so the authors are not to be faulted for their interpretation. 

Since Rluc and GEP recombinantly fused proteins can be expressed in living cells, BRET is an interesting tool for monitoring molecular interactions in cell-based assays. BRET has been particularly used for the study of GPCRs by probing receptor oligomerization or activation. ... 

Heterologous expression systems are the preferred, and in some cases obligate models for stndy of GPCR oligomerization, although high expression levels can lead to nonspecific interactions. 

In the following paragraphs we summarize the current opinion on GPCR oligomerization and provide the details of the accumulated experimental and computational data on GPCR-GPCR interactions. 

Numerous examples of both ligand-induced [98,100-111] and ligand-independent (constitutive) oligomerization [79-81,86,94,96,97,106,112-130] have been reported in the literature over the last few years. However, inferences from these studies have not yet allowed a definitive conclusion about constitutive (i.e., GPCRs exist as stable preformed dimers) or ligand-induced oligomerization. 

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