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RESEARCH PRODUCT
How Can Interleukin-1 Receptor Antagonist Modulate Distinct Cell Death Pathways?
Antonio AbbateAlessandra MagistratoAldo DobrinaAngelo SpinelloElena Vecilesubject
0301 basic medicineProgrammed cell deathProtein ConformationGeneral Chemical EngineeringNecroptosis-Library and Information SciencesMolecular Dynamics SimulationInhibitor of apoptosis01 natural sciencesArticle03 medical and health sciences0103 physical sciencesReceptorsmedicineCaspaseCaspase 8010304 chemical physicsbiologyCell DeathChemistryNeurodegenerationPyroptosisComputational BiologyReceptors Interleukin-1General Chemistrymedicine.diseaseCaspase 9Computer Science ApplicationsCell biologyXIAPEnzyme ActivationInterleukin 1 Receptor Antagonist Protein030104 developmental biologyApoptosisbiology.proteinThermodynamicsInterleukin-1description
Multiple mechanisms of cell death exist (apoptosis, necroptosis, pyroptosis) and the subtle balance of several distinct proteins and inhibitors tightly regulates the cell fate toward one or the other pathway. Here, by combining coimmunoprecipitation, enzyme assays, and molecular simulations, we ascribe a new role, within this entangled regulatory network, to the interleukin-1 receptor antagonist (IL-1Ra). Our study enlightens that IL-1Ra, which usually inhibits the inflammatory effects of IL-1α/β by binding to IL-1 receptor, under advanced pathological states prevents apoptosis and/or necroptosis by noncompetitively inhibiting the activity of caspase-8 and -9. Consensus docking, followed by cumulative 10 μs of molecular dynamics simulations unprecedentedly reveal that IL-1Ra binds both caspases at their dimeric interface, preventing, in this manner, the formation of their catalytically/signaling active form. The resulting IL-1Ra/caspase-8(9) adducts are stabilized by hydrophobic and by few key hydrogen bonding interactions, formed by residues fully conserved across distinct caspases (-3, -6, -7, -8, and -9), and closely resemble the binding mode of the caspases inhibitors XIAP (X-linked inhibitor of apoptosis) and c-FLIP (cellular FLICE-like inhibitory protein). Tight regulation of the different forms of cell death has a major impact on distinct human illnesses (i.e., cancer, neurodegeneration, ischemic injury, atherosclerosis, viral/bacterial infections, and immune reaction). Hence, our study, pinpointing IL-1Ra as new actor of the intricate cell death regulatory network and gaining an atomic-scale understanding of its mechanism may open new avenues toward innovative therapeutic strategies to tackle major human diseases.
year | journal | country | edition | language |
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2018-12-26 |