4lp5
From Proteopedia
Crystal structure of the full-length human RAGE extracellular domain (VC1C2 fragment)
Structural highlights
FunctionRAGE_HUMAN Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. 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.[1] Publication Abstract from PubMedThe receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor sensing endogenous stress signals associated with the development of various diseases, including diabetes, vascular complications, Alzheimer's disease and cancer. RAGE ligands include advanced glycation end-products, S100 proteins, high mobility group box 1 protein and amyloid beta-peptides/fibrils. Their signalling through RAGE induces a sustained inflammation that accentuates tissue damage, thereby participating in disease progression. Receptor oligomerization appears to be a crucial parameter for the formation of active signalling complexes, although the precise mode of oligomerization remains unclear in the context of these various ligands. In the present study, we report the first crystal structure of the VC1C2 fragment of the RAGE ectodomain. This structure provides the first description of the C2 domain in the context of the entire ectodomain and supports the observation of its conformational freedom relative to the rigid VC1 domain tandem. In addition, we have obtained a new crystal structure of the RAGE VC1 fragment. The packing in both crystal structures reveals an association of the RAGE molecules through contacts between two V domains and the physiological relevance of this homodimerization mode is discussed. Based on homology with single-pass transmembrane receptors, we also suggest RAGE dimerization through a conserved GxxxG motif within its transmembrane domain. A multimodal homodimerization strategy of RAGE is proposed to form the structural basis for ligand-specific complex formation and signalling functions, as well as for RAGE-mediated cell adhesion. STRUCTURED DIGITAL ABSTRACT: hRAGE_VC1C2 and hRAGE_VC1C2 bind by x-ray crystallography (View interaction) hRAGE_VC1 and hRAGE_VC1 bind by x-ray crystallography (View interaction). Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products.,Yatime L, Andersen GR FEBS J. 2013 Oct 4. doi: 10.1111/febs.12556. PMID:24119142[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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