4im8

From Proteopedia

(Difference between revisions)

Current revision

low resolution crystal structure of mouse RAGE

Structural highlights

4im8 is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.503Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RAGE_MOUSE Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, phospholipids and glycosaminoglycans (PubMed:21270403, PubMed:32670276). Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. These ligands accumulate at inflammatory sites during the pathogenesis of various diseases, including diabetes, vascular complications, neurodegenerative disorders, and cancers and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction or inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (By similarity). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19901339). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (By similarity). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (By similarity). Promotes also extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (By similarity).[UniProtKB:Q15109][UniProtKB:Q63495]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] Is able to advanced glycosylation end product (AGE)-induce nuclear factor NF-kappa-B activation.^[7] Down-regulates receptor for advanced glycosylation end products (RAGE)-ligand induced signaling through various MAPK pathways including ERK1/2, p38 and SAPK/JNK. Significantly affects tumor cell properties through decreasing cell migration, invasion, adhesion and proliferation, and increasing cellular apoptosis. Exhibits drastic inhibition on tumorigenesis in vitro.^[8]

Publication Abstract from PubMed

RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erk1/2 phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value.

Stable RAGE-Heparan Sulfate Complexes Are Essential for Signal Transduction.,Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD ACS Chem Biol. 2013 May 28. PMID:23679870^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999 Jun 25;97(7):889-901. doi: 10.1016/s0092-8674(00)80801-6. PMID:10399917 doi:http://dx.doi.org/10.1016/s0092-8674(00)80801-6
↑ Gao X, Zhang H, Schmidt AM, Zhang C. AGE/RAGE produces endothelial dysfunction in coronary arterioles in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H491-8. doi:, 10.1152/ajpheart.00464.2008. Epub 2008 Jun 6. PMID:18539754 doi:http://dx.doi.org/10.1152/ajpheart.00464.2008
↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
↑ Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan SS. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 2010 Apr;24(4):1043-55. doi: 10.1096/fj.09-139634. Epub 2009 Nov 11. PMID:19906677 doi:10.1096/fj.09-139634
↑ Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S, Okamoto H, Shimura S, Karasawa T, Yonekura H, Yamamoto H. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011 Mar 1;186(5):3248-57. PMID:21270403 doi:10.4049/jimmunol.1002253
↑ Weinhage T, Wirth T, Schütz P, Becker P, Lueken A, Skryabin BV, Wittkowski H, Foell D. The Receptor for Advanced Glycation Endproducts (RAGE) Contributes to Severe Inflammatory Liver Injury in Mice. Front Immunol. 2020 Jun 3;11:1157. PMID:32670276 doi:10.3389/fimmu.2020.01157
↑ Harashima A, Yamamoto Y, Cheng C, Tsuneyama K, Myint KM, Takeuchi A, Yoshimura K, Li H, Watanabe T, Takasawa S, Okamoto H, Yonekura H, Yamamoto H. Identification of mouse orthologue of endogenous secretory receptor for advanced glycation end-products: structure, function and expression. Biochem J. 2006 May 15;396(1):109-15. doi: 10.1042/BJ20051573. PMID:16503878 doi:http://dx.doi.org/10.1042/BJ20051573
↑ Jules J, Maiguel D, Hudson BI. Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS One. 2013 Nov 8;8(11):e78267. doi: 10.1371/journal.pone.0078267. eCollection, 2013. PMID:24260107 doi:http://dx.doi.org/10.1371/journal.pone.0078267
↑ Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD. Stable RAGE-Heparan Sulfate Complexes Are Essential for Signal Transduction. ACS Chem Biol. 2013 May 28. PMID:23679870 doi:10.1021/cb4001553

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4im8"

@@ Line 1: / Line 1: @@
 ==low resolution crystal structure of mouse RAGE==
-<StructureSection load='4im8' size='340' side='right' caption='[[4im8]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
+<StructureSection load='4im8' size='340' side='right'caption='[[4im8]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4im8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IM8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4im8]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IM8 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ager, RAGE, mCG_5497 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.503&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4im8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4im8 OCA], [http://pdbe.org/4im8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4im8 RCSB], [http://www.ebi.ac.uk/pdbsum/4im8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4im8 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4im8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4im8 OCA], [https://pdbe.org/4im8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4im8 RCSB], [https://www.ebi.ac.uk/pdbsum/4im8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4im8 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/RAGE_MOUSE RAGE_MOUSE] Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, phospholipids and glycosaminoglycans (PubMed:21270403, PubMed:32670276). Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. These ligands accumulate at inflammatory sites during the pathogenesis of various diseases, including diabetes, vascular complications, neurodegenerative disorders, and cancers and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction or inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (By similarity). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19901339). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (By similarity). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (By similarity). Promotes also extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (By similarity).[UniProtKB:Q15109][UniProtKB:Q63495]<ref>PMID:10399917</ref> <ref>PMID:18539754</ref> <ref>PMID:19901339</ref> <ref>PMID:19906677</ref> <ref>PMID:21270403</ref> <ref>PMID:32670276</ref>   Is able to advanced glycosylation end product (AGE)-induce nuclear factor NF-kappa-B activation.<ref>PMID:16503878</ref>   Down-regulates receptor for advanced glycosylation end products (RAGE)-ligand induced signaling through various MAPK pathways including ERK1/2, p38 and SAPK/JNK. Significantly affects tumor cell properties through decreasing cell migration, invasion, adhesion and proliferation, and increasing cellular apoptosis. Exhibits drastic inhibition on tumorigenesis in vitro.<ref>PMID:24260107</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Lk3 transgenic mice]]
+[[Category: Large Structures]]
-[[Category: Chazin, W J]]
+[[Category: Mus musculus]]
-[[Category: Corbett, K D]]
+[[Category: Chazin WJ]]
-[[Category: Esko, J D]]
+[[Category: Corbett KD]]
-[[Category: Krahn, J M]]
+[[Category: Esko JD]]
-[[Category: Pedersen, L C]]
+[[Category: Krahn JM]]
-[[Category: Song, D]]
+[[Category: Pedersen LC]]
-[[Category: Xu, D]]
+[[Category: Song D]]
-[[Category: Young, J H]]
+[[Category: Xu D]]
-[[Category: Heparan sulfate]]
+[[Category: Young JH]]
-[[Category: Signaling protein]]

4im8

From Proteopedia

Current revision

low resolution crystal structure of mouse RAGE

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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