Solution Structure of the Soluble Receptor for Advanced Glycation End Products (sRAGE)

Sárkány, Zsuzsa; Ikonen, Teemu P.; Ferreira-da-Silva, Frederico; Saraiva, Maria João; Svergun, Dmitri I.; Damas, Ana M.

doi:10.1074/jbc.m111.223438

Cited by 38 publications

(41 citation statements)

References 31 publications

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“…Thus, RAGE is likely to integrate combinations of inflammatory stimuli, and drive appropriately adjusted immune responses. The activity of RAGE is also regulated by concentration and metal ion-dependent cis-or trans-homodimerization (Koch et al, 2010;Sárkány et al, 2011) and the soluble RAGE form has been shown to interfere with RAGE dimerization and signaling (Hofmann et al, 1999;Bierhaus et al, 2001). Thus, fine-tuning of RAGE activation is likely an important mechanism for timely detection of microbes and sterile tissue damage.…”

Section: Rage-deficient Mice Have Impaired Inflammatory Responses To mentioning

confidence: 99%

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

Sirois¹,

Jin²,

Miller³

et al. 2014

Journal of Experimental Medicine

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Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.

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Section: Rage-deficient Mice Have Impaired Inflammatory Responses To mentioning

confidence: 99%

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

Sirois¹,

Jin²,

Miller³

et al. 2014

Journal of Experimental Medicine

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“…Thus, RAGE, a pattern recognition receptor [35–37], may recognize negative charge and/or hydrophobicity on its ligands. There are several positively charged patches on the V-domain of RAGE, including Arg-29, Lys-37, Lys-39, Lys-43, Lys-44, Arg-48, Lys-52, Arg-98, Arg-104, Lys-107, Lys-110, Arg-114 and Arg-116 [33,38,39], which may form two main regions [39] that interact with negatively charged regions of RAGE ligands (e.g., Aβ, S100 proteins, age-modified compounds and HMGB1) (Figure 2B). RAGE also has a number of hydrophobic pockets, which include residues Ile-26, Ala-28, Ile-30, Pro-33, Leu-34, Val-35, Leu-36, Trp-61, Val-63, leu-64, Trp-72, Val-75, Val-78, Leu-79, Pro-80, Phe-85, Leu-86, Pro-87, Ala-88, val-89, Ile 91 and Tyr-118 [33,39].…”

Section: Structure–function Relationship Of Ragementioning

confidence: 99%

“…In a mouse model of AD, PD-hAPP, sRAGE increased CBF and reduced neuroinflammation and brain Aβ levels by acting as a decoy receptor that sequesters the Aβ and preventing it from interacting with membrane bound RAGE [5]. However, RAGE is known to self-associate and forms oligomers via the C1 domain [2,38]. Ligand binding may stabilize the RAGE oligomers that lead to transmembrane cell signaling.…”

Section: Rage Isoformsmentioning

confidence: 99%

“…Ligand binding may stabilize the RAGE oligomers that lead to transmembrane cell signaling. It is also possible that binding of sRAGE to cell membrane bound RAGE, due to RAGE hetero-oligomerization, prevents Aβ binding to the V-C1 domain [2,38]. Levels of sRAGE may play a role in chronic disorders, such as cardiovascular, inflammatory, diabetes and AD.…”

Section: Rage Isoformsmentioning

confidence: 99%

“…sRAGE may act as a decoy receptor, which reduces ligand binding to cell surface RAGE, and thereby regulating the activity of RAGE. It may also form hetro-oligomers by interacting with cell surface bound RAGE [2,38]. While the use of sRAGE as a potential therapeutic approach has been tested in rodent modes of AD and diabetes, its efficacy and safety in larger animal models is yet to be determined.…”

Section: Rage As a Therapeutic Targetmentioning

confidence: 99%

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Is RAGE Still A Therapeutic Target For Alzheimer’s Disease?

Deane

2012

Future Med. Chem.

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The receptor for advanced glycation end products (RAGE) is a multiligand receptor involved in inflammatory disorders, tumor outgrowth, diabetic complications and Alzheimer's disease (AD). RAGE transports circulating amyloid-β toxins across the blood–brain barrier (BBB) into the brain. RAGE–amyloid-β toxin interaction at the BBB leads to oxidative stress, inflammatory responses and reduced cerebral blood flow. Thus, regulating RAGE activity at the BBB and/or within brain could be beneficial to AD patients. Herein, the structure–function relation for RAGE–ligand interaction and the role of RAGE as a potential target in the development of treatments for AD and other RAGE-associated disorders are discussed. Despite recent setbacks in the development of RAGE-based therapies for AD, a new generation of compounds that regulate RAGE activity could be efficacious. Careful studies are needed in rodent and nonrodent animal models of AD with new the generation of RAGE antagonists to ensure safety and efficacy in chronic treatment before clinical trials.

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