Dimerization of chemokine receptors and its functional consequences
Introduction
Chemokine receptors belong to the family of G protein-coupled receptors (GPCR), or seven transmembrane domain (7TM) receptors, encoded by one of the largest gene families in the human genome [1], [2], [3]. Altogether, these receptors constitute the targets for about half the therapeutic agents used presently, and many receptors discovered over the last 10 years, including most of the chemokine receptors, have been incorporated in drug development programs [4], [5]. Given the high interest of this receptor family for human therapy, numerous studies have attempted to delineate the tridimensional structure of these proteins, and their structure–function relationships. However, the only actual GPCR structure known so far is that of bovine rhodopsin [6], [7], [8], [9]. Also, the dimeric nature of this class of receptors has essentially remained ignored up to relatively recently. It is however largely accepted nowadays that most, if not all, GPCRs form dimers or higher order oligomers, and that this oligomeric structure might be essential for their functional properties. The prominent current hypothesis is indeed that GPCRs assemble as dimers shortly after synthesis in the endoplasmic reticulum, and traffic as such throughout their life in the cell. The present review concentrates onto the recent developments in the frame of oligomerization of chemokine receptors, and what is known regarding its relation to receptor activation and the functional consequences of this process. Other excellent reviews have recently addressed the field of GPCR oligomerization in general [10], [11], [12], [13], [14], [15].
Section snippets
Chemokines and chemokine dimerization
The chemokine family includes more than 40 members, classified into two major subfamilies (CC and CXC) and two minor subfamilies (C and CX3C) [16]. NMR spectroscopy and X-ray crystallography studies have provided high-resolution structures for a number of chemokines, revealing a conserved fold across subfamilies [17], [18], [19], [20], [21], [22], [23], [24]. This common fold is composed of a three stranded anti-parallel β-sheet covered on one face by a C-terminal α-helix and preceded by a
Chemokine receptors
Nineteen functional chemokine receptors have been reported so far. They constitute a structurally distinct subfamily among the class A of GPCRs. Chemokine receptors bind either CC-, CXC-, XC or CX3C-chemokines and are classified into four families on the basis of their ligand-binding properties. These receptors play a key role in the basal trafficking of leucocytes and their recruitment to inflammatory sites. They are therefore involved in the physiopathology of all inflammatory diseases. In
Dimerization of G protein-coupled receptors
Until the past few years, GPCRs were essentially considered as monomeric functional structures. A growing body of evidence has however accumulated recently, which support that GPCRs exist and function essentially as dimers or higher order oligomers. A number of recent reviews have addressed this question [10], [11], [12], [13], [14], [15].
Oligomerization of chemokine receptors
Oligomerization was reported for four chemokine receptors so far: CCR2, CCR5, CXCR2 and CXCR4. Co-immunoprecipitation, BRET and FRET experiments have shown unambiguously that CCR2 and CCR5 are able to form both homo- and heterodimers [100], [101], [102], [103], [104], [105]. Subcellular fractionation followed by BRET measurement has suggested that homodimerization of CCR5 occurs shortly after synthesis in the endoplasmic reticulum [102]. This is consistent with similar observations made for
Functional consequences of receptor dimerization
The reported functional consequences of dimerization vary greatly according to the specific GPCR dimer considered. In most cases, no clear functional consequences have been associated with the demonstration of a dimerization process. In some situations, heterodimers were reported to display pharmacological profiles, G protein coupling, and/or regulation mechanisms which are different from those of their homodimer counterparts. In only a few cases, the heterodimerization of two distinct
Receptor dimerization and HIV infection
The potential oligomeric status of the HIV co-receptors CCR5 and CXCR4 has rapidly caught the attention of different groups, who have tried to address the relationships between the receptor dimerization status, their role as co-receptor and HIV infectivity. Vila-Coro et al. have reported that a mAb directed against CCR5 N-terminus neither competed with chemokine nor with gp120 binding, but blocked HIV-1 replication in vitro and in vivo [108]. As this mAb was shown to promote receptor
Contact interface between protomers
An important issue in the understanding of dimeric GPCR function is certainly the identification of the structural determinants required for oligomerization. The various GPCR families display very diverse ligand binding domains and significant sequence variation. It is likely that their common TM bundle, which contains most conserved structural motifs, is primarily involved in the dimerization process. Various transmembrane domains have been suggested to contribute to the dimerization of
Perspectives
The fact that G protein-coupled receptors in general and chemokine receptors in particular, are able to form dimers is now well established. Although dimerization was formally demonstrated for CCR2, CCR5, CXCR2 and CXCR4 only, it is very likely that all chemokine receptors function as homodimers. Heterodimerization has been unambiguously demonstrated for the closely related CCR5 and CCR2, but also between CCR2 and CXCR4, and has been suggested between CCR5 and the opiate receptors. Whether this
Acknowledgements
The work performed in the authors’ laboratory was supported by the Belgian programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming, the LifeSciHealth (grant LSHB-CT-2003-503337) programme of the European Community, the Fonds de la Recherche Scientifique Médicale of Belgium, Fortis, the French Agence Nationale de Recherche sur le SIDA and the Fondation Médicale Reine Elisabeth. The scientific responsibility is assumed
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