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Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors

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Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors International Journal of Molecular Sciences Review Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors Hyeon Jin Kim 1 , Mi Suk Jeong 2,* and Se Bok Jang 1,* 1 Department of Molecular Biology, College of Natural Sciences, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan 46241, Korea; [email protected] 2 Insitute for Plastic Information and Energy Materials and Sustainable Utilization of Photovoltaic Energy Research Center, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan 46241, Korea * Correspondence: [email protected] (M.S.J.); [email protected] (S.B.J.); Tel.: +82-51-510-2523 (M.S.J. & S.B.J); Fax: +82-51-581-2544 (M.S.J. & S.B.J.); Abstract: Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases. Keywords: RAGE; multi-ligands; disease; drug; inhibitor Citation: Kim, H.J.; Jeong, M.S.; Jang, S.B. Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors. Int. J. Mol. 1. Introduction Sci. 2021, 22, 6904. https://doi.org/ RAGE (receptor for advanced glycation end-products) was first isolated from the hu- 10.3390/ijms22136904 man lung library in 1992 and noted for its ability to act as a receptor for advanced glycation end products (AGEs). RAGE is a transmembrane protein of the immunoglobulin (Ig) super- Academic Editor: Béatrice Charreau family of cell surface molecules [1], and interacts with multiple ligands that mediate cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as Received: 26 May 2021 AGEs, the S100 group of proteins, HMGB1 (high mobility group box-1 protein), amyloid Accepted: 24 June 2021 β, and DNAs, and also acts as an innate immune sensor of PAMPs (pathogen-associated Published: 27 June 2021 molecular pattern molecules), such as bacterial LPS, respiratory viruses, viral and parasitic proteins, and bacterial DNA [2–12]. Ligand stimulation of RAGE activates signal trans- Publisher’s Note: MDPI stays neutral duction pathways, such as the diaphanous-related formin 1 (DIAPH1), mitogen-activated with regard to jurisdictional claims in protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, and Toll-interleukin published maps and institutional affil- 1 receptor domain-containing adaptor protein (TIRAP) pathways, which result in RAGE- iations. dependent NF-κB activation [13–19]. RAGE is expressed in many cell types, including endothelial, vascular smooth muscle, and cancer cells monocyte/macrophages, granulo- cytes, and adipocytes [20]. Upregulated RAGE expression has been reported in diabetes mellitus, atherosclerosis, rheumatoid arthritis, Alzheimer’s disease (AD), cardiovascular Copyright: © 2021 by the authors. diseases (CVDs), and immune/inflammatory diseases [21–25], and has also been shown to Licensee MDPI, Basel, Switzerland. be related to the developments and progressions of different cancer types [26]. This article is an open access article distributed under the terms and 2. Structure and Isoforms of RAGE conditions of the Creative Commons RAGE is a 50–55 kDa glycosylated protein that contains an extracellular (amino acids Attribution (CC BY) license (https:// 23–342), a hydrophobic transmembrane (residues 343–363), and a cytoplasmic (residues creativecommons.org/licenses/by/ 4.0/). 363–404) domain. The extracellular structure of RAGE is composed of a variable (V) Int. J. Mol. Sci. 2021, 22, 6904. https://doi.org/10.3390/ijms22136904 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6904 2 of 22 immunoglobulin (Ig) domain (residues 23–116) and two constant C1 (residues 124–221) connected to C2 (residues 227–317) Ig domains by a flexible seven amino acid linker [27]. Its V domain consists of eight strands (A’, B, C, C’, E, F, and G) connected by six loops that form two beta-sheets linked by a disulfide bridge between Cys38 (strand B) and Cys99 (strand F) [28]. The molecular surfaces of V-C1 domains are covered by a hydrophobic cavity and contain many highly positively charged Arg and Lys residues [17]. In contrast, the C2 domain is composed of acidic amino acids and carries a negative surface charge (Figure1)[29]. Multiple RAGE ligands contain highly negatively charged regions and can bind to the positively charged V-C1 domain [7]. Ding Xu reported that heparan sulfate plays a crucial role in stabilizing RAGE homodimerization the self-association of V-V do- mains and RAGE hexamerization [30]. In its monomeric state, RAGE has only weak affinity for several ligands, and thus, it appears that its multimerization is necessary for ligand binding. RAGE oligomerizations through its C1-C1 domains, C2-C2 domains, and/or TM helix dimerization are important steps for RAGE signaling after ligand binding [30–32]. The transmembrane helical structure of RAGE contains the meticulously conserved GxxxG motif, which promotes helix-helix homodimerization and may be involved in signal trans- duction [33]. The cytoplasmic domain of RAGE exhibits high sequence identity with primates and rodents, which is essential for RAGE ligand-mediated signal transduction [1], and its cytoplasmic domain contains a highly acidic region that is capable of binding several molecules. In fact, truncation of this domain abolishes downstream RAGE signaling and attenuates RAGE-associated pathologic effects [34,35]. The human RAGE gene is located on chromosome 6 in the MHC (major histocom- patibility complex) class III region, which contains many genes that impact the adaptive and innate immune systems [29]. More than 20 RAGE isoforms with diverse biological functions have been found to result from alternative splicing [36]. In addition, poly- morphisms in RAGE have been suggested to be potential biomarkers in RAGE-relevant diseases [37,38], and the RAGE transcript has been identified as the target for the pro- ductions of alternative splicing generates isoforms, such as full-length RAGE (FL-RAGE), dominant-negative RAGE (DN-RAGE, residues 23–363), N-truncated RAGE (N-RAGE, 124–404), C-truncated soluble RAGE (sRAGE, 23–342), and splice variant endogenous secretory RAGE (esRAGE) [39]. The functions of these truncated RAGE isoforms have yet to be elucidated, but it has been established the dysregulations of RAGE isoforms and their ligands lead to the development of a number of human diseases [40,41]. Soluble RAGE may competitively inhibit RAGE-ligand-mediated signaling, and a low sRAGE level has been suggested to be a biomarker for diseases [7]. On the other hand, serum levels of sRAGE in diabetes, sepsis, and end-stage renal disease (ESRD) are elevated [42,43]. Int. J. Mol. Sci. 2021,Int. 22, J.x Mol.FOR Sci.PEER2021 REVIEW, 22, 6904 3 of 23 3 of 22 (A) (B) (C) Figure 1. StructuralFigure 1. Structural analyses ofanalyses RAGE. of (A RAGE.) Schematic (A) Schematic representation representation of full-length of full-length RAGE domain. RAGE domain. RAGE consists of a variable (V)RAGE domain, consists two of constant a variable (C1 (V) and domain, C2) domains, two constant a transmembrane (C1 and C2) domains, region, and a transmembrane a cytoplasmic tail.re- (B) RAGE isoforms. RAGEgion, and isoforms a cytoplasmic in the illustration tail. (B) RAGE include isoforms. (from left RAGE to right) isoforms full-length in the RAGE,illustration oligomers, include dominant-negative (from left to right) full-length RAGE, oligomers, dominant-negative RAGE (DN-RAGE), N-truncated RAGE (DN-RAGE), N-truncated RAGE (N-RAGE), endogenous secretory (esRAGE), and soluble form RAGE (sRAGE). RAGE (N-RAGE), endogenous secretory (esRAGE), and soluble form RAGE (sRAGE). (C) The sur- (C) The surface of RAGE colored according to electrostatic charges (PDB ID: 4YBH). Positively charged areas are shown in face of RAGE colored according to electrostatic charges (PDB ID: 4YBH). Positively charged areas blue, and negativeare shown charged in blue, areas and innegative red. The charged figure wasareas prepared in red. The using figu PyMOL.re was prepared using PyMOL. 3. RAGE as a Multi-Ligand Receptor The human RAGE gene is located on chromosome 6 in the MHC (major histocom- patibility complex) classRAGE III bindsregion, diverse which classescontains of many ligands, genes such that as HMGB1,impact the S100 adaptive calcium-binding pro- tein/calgranulin, amyloid-β, and lysophosphatidic acid (LPA) [3,5,22,44–47]. RAGE ex- and innate immune systems [29]. More than 20 RAGE isoforms with diverse biological pression can also increase DNA internalization and augment the Toll-like receptors (TLR) functions have been found to result from alternative splicing [36]. In addition, polymor- response through TLR9 [48,49]. Ligand engagement of RAGE activates multiple signaling phisms in RAGE have been suggested to be potential
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