Browsing by Subject "Interleukin-18"

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Open Access
A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers
(Elsevier, 2023-07-01) Yazıcı, Yılmaz Yücehan; Belkaya, Serkan; Timuçin, E.
Interleukin 18 (IL18) is a pro-inflammatory cytokine that modulates innate and adaptive immune responses. IL18 activity is tightly controlled by the constitutively secreted IL18 binding protein (IL18BP). PDB structures of human IL18 showed that a short stretch of amino acids between 68 and 81 adopted a disordered conformation in all IL18-IL18BP complexes while adopting a 310 helical structure in other IL18 structures, including the receptor complexes. The C74 of human IL18, which was reported to form a novel intermolecular disulfide bond in the human tetrameric assembly, is also located in this short epitope. These observations reflected the importance of this short surface epitope for the structure and dynamics of the IL18-IL18BP heterodimers. We have analyzed all known IL18-IL18BP complexes in the PDB by all-atom MD simulations. The analysis also included two computed complex models adopting a helical structure for the surface epitope. Heterodimer simulations showed a stabilizing impact of the small surface region at the helical form by reducing flexibility of the complex backbone. Analysis of the symmetry-related human IL18-IL18BP tetramer showed that the unfolding of this small surface region also contributed to the IL18-IL18BP stability through a completely exposed C74 sidechain to form an intermolecular disulfide bond in the self-assembled human IL18-IL18BP dimer. Our findings showed how the conformation of the short IL18 epitope between amino acids 68 and 81 would affect IL18 activity by mediating the intermolecular interactions of IL18.
Open Access
Investigation of human IL18 structures towards understanding the dynamics and self-assembly of IL18-IL18BP heterodimers
(2023-08) Yazıcı, Yılmaz Yücehan
Interleukin-18 (IL18) is an inflammatory cytokine involved in the regulation of both innate and adaptive immunity. IL18 activity is tightly regulated by its constitutively secreted inhibitor, IL18 binding protein (IL18BP). All known IL18BPs from human to poxviruses share an identical protein fold. Investigation of known crystal structures of human IL18 illustrated that the region between the 68th and 81st amino acids is either missing or disordered in all IL18-IL18BP complexes while adopting a 310 helical structure in the free or signaling complexes of IL18. The C74 residue in this region was reported to form a novel intermolecular disulfide bond in the human IL18-IL18BP tetrameric assembly. Yet, the impact of this small surface epitope on the stability and self-assembly of IL18 is unclear. First, we investigated the dynamics of this small surface region of IL18-IL18BP heterodimers by molecular dynamics simulations. In simulations, we used all known crystal structures of IL18-IL18BP and two additional computer models generated by AlphaFold2 and homology modeling to observe the differential folding of small surface regions. Next, we generated the proposed human and Yaba-like disease virus tetramers and analyzed them with or without intermolecular disulfide bonds. We found that the helical structure of small surfaces stabilizes the backbone of the complex through reducing its flexibility. While our computational model folded into a more stable and less flexible short IL18 epitope, similar to free IL18 or bound IL18 on the signal complex, IL18 from the complexes with human or virus IL18BPs displayed flexible regions with a less stable backbone. The core of the human crystal loosened, becoming more exposed to solvent in the human crystal structure. Particularly, a salt bridge stabilized the human IL18 structure at the helix configuration, linking the helix to the core region. We observed that the bivalent binding mode for the human tetramer, which is disturbing one side of the tetramer by breaking the disulfide bonds, did not affect the stability of the complex, and thereby the tetramer remained intact. Hence, the tetramer formation of IL18-IL18BP can be beneficial to the host as it provides an additional stability advantage. Overall, our results show that the short IL18 epitope between the amino acids 68 and 81 mediates stability and self-assembly of IL18-IL18BP heterodimers.