Identification and biological significance of G protein-coupled receptor associated sorting proteins (GASPs)
Introduction
G protein-coupled receptors (GPCRs) represent one of the most abundant protein families encoded by the human genome. By the most recent estimations there are a total of 799 sequence verified human GPCRs, of which 369 respond to endogenous ligands (see Lagerstrom & Schioth, 2008). These ligands display an extraordinary diversity, including amino acids, Ca2+ ions, peptides, lipid-like substances and large glycoprotein hormones. In animals, all physiological functions are modulated by complex equilibriums between different subsets of GPCRs. From a pharmaceutical point of view, these receptors are targeted by around 40% of all drugs available on the market (see Jacoby et al., 2006, Eglen et al., 2007). Noticeably, these compounds act through less than 50 different GPCRs leaving more than 300 receptors as potential targets for the development of therapeutic agents (see Lagerstrom & Schioth, 2008).
The activity of GPCRs is tightly regulated. Particularly, they interact with a vast repertoire of GPCR interacting proteins (GIPs) that display important functions, including the targeting of receptors to specific subcellular compartments, their trafficking to and from the plasma membrane and the fine-tuning of their signalling properties (see Bockaert et al., 2004). Consequently, if we want to discover and optimize new therapeutic agents targeting GPCRs we must appreciate the functioning of these novel interacting partners.
With the exception of arrestins, for which the interaction with numerous GPCRs has been largely demonstrated (see Pierce et al., 2002), most GIPs modulate the function of only one or a small subset of GPCRs. Some are transmembrane proteins while other are cyto-soluble and mainly interact with the C-terminal tail (C-tail) of receptors. In this review, we will describe the discovery and potential functions of a novel family of proteins, the so-called GPCR associated sorting proteins (GASPs). Like arrestins, they display a broad spectrum of interaction with GPCRs and may therefore represent an important family of proteins regulating GPCR physiology.
Section snippets
Discovery of GASPs
The first member of the GASP family was originally identified by a Japanese group using the PAS domain of rat Period1 as bait in a two-hybrid screen of a cDNA library from rat suprachiasmatic nucleus (Matsuki et al., 2001). This protein was therefore called PIPS (Period1 interacting protein of the suprachiasmatic nucleus). It was further shown to display a strong sequence homology with a human protein, KIAA0443, identified at the Kazusa DNA Research Institute in a project aiming to identify
GASPs are members of a single gene family
Despite the lack of homogeneity in the official nomenclature, as discussed above, there is a variety of evidences showing that GASP-1 to -10 belong to the same protein family. First of all, GASP-1 to -10 display significant sequence similarities. As shown in Fig. 1, they share a conserved C-terminal domain of 250 amino acids. This region displays 20 to 77% sequence identity in pairwise comparisons between GASP-1 and other GASPs. In addition, we have identified a highly conserved and repeated
Functions of GASPs
Although no clear molecular function has been assigned to this protein family, several studies point to their implications in at least two different cellular activities.
GASPs and diseases
There are few reports of GASPs in pathological situations. Most of them are based on transcriptomic studies showing alteration of mRNA levels of different GASPs. Except for two studies, one showing that GASP-3 mRNA level is decreased in the brain of Alzheimer's disease patients (Heese et al., 2004), and a second one that places GASP-4 in a list of 892 highly dysregulated priority genes in the brain of Parkinson's disease patients (Moran & Graeber, 2008), all other reports describe the possible
Conclusion
Despite their very different sizes, ranging from 249 to 1395 amino acids, GASPs share many common features both in terms of sequence similarities, gene organization and functions. The GASP subfamily 1 is clearly involved in the modulation of GPCR activity and could modulate transcription, while the GASP subfamily 2 is mostly involved in the modulation of transcription, particularly through interactions with known transcription factors. Considering these two functions, it is tempting to
Acknowledgments
This study was supported by The Centre National de la Recherche Scientifique and the Université de Strasbourg (AA and FS), the Association pour la Recherche sur le Cancer (FS, no. 3423), Fondation pour la Recherche Médicale (FS) and a fellowship from Société Française de Pharmacologie et de Thérapeutique (AA). We thank Renaud Wagner and Jeremy Garwood for critical reading of the manuscript.
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