X- ray diffraction by crystals
4.2 Structure and ligand-binding properties of RAGE
4.2.2 Mechanisms for activation and blocking of RAGE
Up to now it is rarely understood how RAGE is activated and functions in cellular signaling.
RAGE is composed of a large extracellular ligand-binding region, a short transmembrane helix, and a highly acidic 43 amino acid long cytoplasmic domain essential for intracellular RAGE signaling (Huttunen et al., 1999). DN-RAGE is the truncated form of the receptor that is devoid of the cytoplasmic tail but has intact transmembrane-spanning and extracellular domains. In vitro studies with transformed mouse microglial cells showed that introduction of DN-RAGE prevented RAGE mediated cellular activation by S100B, even in the presence of endogenous wild-type receptor (Hofmann et al., 1999). This dominant negative effect on RAGE-dependent signaling could also be demonstrated in numerous cell and animal studies
-CONCLUSIONS- al., 2003). Remarkably, this intracellular region of RAGE is very small and has little
persistent secondary or tertiary structure (Dattilo et al., 2007). Despite being so small and unstructured, a recent study revealed that ERK kinases bind directly to this cytoplasmic tail (Ishihara et al., 2003). But still the mechanism how the signal is transduced to the intracellular domain remains unclear. By the molecular architecture with structurally inter-dependent V and C1 domains and a structurally autonomous C2 domain with rotational freedom, it is unlikely that the signal is transduced via C2 domain and the transmembrane helix to the intracellular domain. Therefore, it is proposed that RAGE signaling is mediated by ligand-induced receptor oligomerization. This was already suggested based on the hexameric structure of S100A12 (Moroz et al., 2002). The authors propose that three dimers (six subunits) of S100A12 bind three molecules of RAGE. A similar model is described for S100B where a tetrameric form (two dimers) of S100B binds to V domain of RAGE (Ostendorp et al., 2007). Such a receptor multimerization has been established as a general mechanism for the initiation of signal transduction. Many cell-surface receptors are activated by a ligand-induced multimerization process, such as Toll-like receptors (de Bouteiller et al., 2005; Hu et al., 2004) or the receptor for tumor necrosis factor α (Bazzoni et al., 1995).
An activation mechanism via RAGE dimerization is consistent with the arrangement of V-C1 molecules in the crystal. Two molecules arrange side-by-side via C1 domain. This molecular composition involves numerous hydrogen bonds as well as polar interactions (3.5 Figure 4). Interestingly, there exists a second interaction site via a bridging Zn2+ adjacent to the site mentioned above. The Zn2+ is coordinated by His180 and Glu182 from one molecule and His185’ from the other molecule. The coordination is completed by an acetate molecule derived from the crystallization buffer. Based on this pronounced interaction of two V-C1 molecules in the crystal, SPR experiments were performed to analyze the kinetic properties and the dependence on Zn2+ of this interaction. Actually, binding of V-C1 domains to V-C1 domains was observed with, as well as without Zn2+ (3.5 Figure 1 D and E). Nevertheless, Zn2+ considerably influences the kinetic properties of the interaction. Whereas the association is similar, dissociation is much faster in the absence of Zn2+. Hence, in the presence of Zn2+
the affinity is about 4-fold higher (Kd value: ~2 µM) than in the absence of Zn2+ (Kd value:
~0.5 µM). Notably, the extracellular Zn2+ concentration can reach 0.5-1 mM (Fraker and Telford, 1997). Thus, it can be assumed that a Zn2+-dependent interaction also occurs in vivo.
Compared to previous studies this study for the first time gives evidence of a dimerization of RAGE. Analytical ultracentrifugation has been used to show that bacterially expressed
-CONCLUSIONS- consistent with the initial purification of RAGE (Schmidt et al., 1992) and has been
corroborated by studies with mouse RAGE and recombinant sRAGE from yeast (Hanford et al., 2004; Ostendorp et al., 2006). However, the kinetic analysis of the complex formation suggests that these dimers are not stable enough to be detected in solution. Based on these findings the current hypothesis for RAGE activation is that bound ligands stabilize a dimeric or even higher multimeric state of RAGE. Thereby, the cytosolic domains of RAGE approximate which induces the formation of a signaling platform (3.5 Figure 7). This complex then activates the signal transducing cascade. Furthermore, with this model blocking of RAGE can be explained as well. RAGE isoforms with a truncated C-terminus, representing the intracellular signaling domain, have a dominant negative effect on RAGE activation.
Treatment with exogenous sRAGE has been shown to effectively block RAGE-dependent signaling (Park et al., 1998). This can be explained by ligand binding to wild-type RAGE and a C-terminally truncated isoform of RAGE. Such a complex can not form the required signaling platform and signal transduction is aborted (3.5 Figure 7). This clearly demonstrates the potential of RAGE as a therapeutic target in a various number of diseases (Bierhaus et al., 2006; Hudson and Schmidt, 2004), by blocking the association of RAGE.
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