The Correlation Between Signaling And Allostery In Type ? Cytokines:dynamics Simulation Of IL-21 Receptors And Prediction Of Allosteric Regions Of IL-2

Interleukin-21(IL-21)and interleukin-2(IL-2)belong to a family of type I cytokine that modulate the immune system and induce the division and proliferation of their target cells.The binding of IL-21 to its receptors activates the receptors,triggering a series of downstream signaling events.The mechanism of signal transduction by its receptors remains obscure.In addition,the discovery of high potency mutant of IL-2 did not explain the structural changes caused by residue mutations.We first analyze the conformational changes in the IL-21 receptors from inactive to activate state in terms of structure,aiming to understand how IL-21 performs multiple immune regulatory functions by different signaling pathways.The IL-21 receptors consist of two heterologous receptor chains:the specific receptor IL-21R? for IL-21 and the common gamma chain receptor IL-21Ry.In this paper,we studied the conformations of transmembrane and intracellular domains of IL-21 receptors at rest and the structural changes caused by allosteric effects in IL-2.The details are as follows:(1)We modeled the transmembrane helices of IL-21R? and IL-21R? receptors using computational approach.We simulated the helical dimerization of transmembrnae regions in a 1,2-dihexadecanoyl-rac-glycero-3-phosphocholine(DPPC)bilayer membrane environment by molecular dynamics simulations,obtaining a stable dimeric conformation of the transmembrane domains.The transmembrane domain is an important bridge of transmembrane signaling.The possible conformation of the transmembrane domains at resting state can help us understand the molecular mechanism of receptor activation.(2)The interaction of intracellular domains and cell membrane in many kinds of cytokine receptors has been reported,and the membrane-mediated regulation of receptor signaling is widely concerned.We used computational methods combined with experimental techniques(surface plasmon resonance,nuclear magnetic resonance)to investigate the interaction of IL-21 R? receptor intracellular domain with cell membrane phospholipids.The results showed that the intracellular domain can specifically interact with acidic phospholipids,indicating that the intracellular domain of IL-21R? receptor is likely to bind to the cell membrane.(3)Nuclear magnetic resonance experiments show that the impact of amino acid residue mutations can be transmitted in the dynamic network of cyclophilin A,reaching the regions away from the mutation sites.We used computational methods to analyze the dynamic networks in protein CypA,and validated the calculated results.In addition,we further analyzed the dynamic networks in IL-2 and IL-1?.We examined the structural deviations of wild-type and mutant proteins and found that structural changes caused by residue mutations tended to occur in dynamic networks,confirming the association of protein structures with their dynamic networks.