9s2x
Crystal structure of the human RAGE ectodomain in complex with murine S100A6 mutant Y84C
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 PubMedExtracellular S100 proteins act as alarmins and trigger pro-inflammatory signaling cascades by activating cognate cell-surface receptors such as the receptor for advanced glycation end-products (RAGE), thereby contributing to both normal and pathological inflammation depending on the physiological context. These ligand-receptor interactions occur in an oxidative environment that is known to induce post-translational modifications, notably on the cysteine residues present in S100 proteins, giving rise to disulfide-crosslinked S100 species. The fine molecular architecture of these S100 covalent assemblies and their impact on the interaction of S100 with RAGE remains poorly characterized, as most in vitro studies employ cysteine variants or reducing conditions. In this study, a thorough analysis of cysteine conservation within the whole S100 family shows an enriched presence of cysteines in the second half of helix H4, with a hotspot for cysteine occupancy at position 84. Following the introduction of a cysteine at this conserved position in S100A6, SDS-PAGE analysis under nonreducing conditions shows a noteworthy amount of covalent S100A6 Y84C dimer in solution, and the structural analysis of the resulting complex with the RAGE ectodomain reveals the formation of a covalent Cys84-Cys84 linkage between the two S100A6 protomers, thus stabilizing the dimeric conformation of RAGE-bound S100A6. Modeling of other S100 proteins that naturally bear a Cys84 in the RAGE-bound conformation suggests that this covalent S100 dimer architecture may be adopted by other members of the family previously reported to form disulfide-crosslinked species. Altogether, these findings provide a first possible model for S100 covalent homodimerization that is fully compatible with RAGE binding. A first structural model for covalent dimerization of S100 proteins.,Demou M, Yatime L Acta Crystallogr F Struct Biol Commun. 2026 May 1;82(Pt 5):176-83. doi: , 10.1107/S2053230X26002992. PMID:41978530[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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