7al7
From Proteopedia
The Crystal Structure of Human IL-18 in Complex With Human IL-18 Binding Protein
Structural highlights
DiseaseI18BP_HUMAN Disease susceptibility may be associated with variants affecting the gene represented in this entry. FunctionI18BP_HUMAN Isoform A binds to IL-18 and inhibits its activity. Functions as an inhibitor of the early TH1 cytokine response.[1] [2] [3] Publication Abstract from PubMedHuman Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease. Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity.,Detry S, Andries J, Bloch Y, Gabay C, Clancy DM, Savvides SN J Biol Chem. 2022 May;298(5):101908. doi: 10.1016/j.jbc.2022.101908. Epub 2022 , Apr 6. PMID:35398099[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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