RAGE and Its Splice Variants
Human RAGE is encoded by a gene located on major histocompatibility complex (MHC) class III region on chromosome 6 [11]. The mature RAGE has three main parts, consisting of extracellular, transmembrane, and cytosolic regions. The extracellular region is composed of one V-type and two C-type domains, and the V-type domain is responsible for interaction with multiple RAGE ligands. The transmembrane domain anchors RAGE to the cellular membrane, and signals transduce into the cell via the cytosolic domain [1, 12]. Besides, RAGE variants, represented by three forms, called N-truncated, dominant-negative, and soluble RAGE, can be generated either by natural alternative splicing or by the action of membrane-associated proteases (Fig. 1) [1]. The N-truncated form of RAGE lacks a V-domain so that it can not interact with ligands, whereas the cytosolic domain is missing in dominant-negative RAGE, which results in no signal transduction, though it can bind to ligands. Without the transmembrane domain, soluble RAGE is formed and is able to circulate out of the cell and act as decoys by preventing ligands from binding to RAGE [13]. Therefore, soluble RAGE can neutralize the effect of RAGE ligands, and many studies have suggested that this function might be applied to inhibition of RAGE signals in human diseases [14].