Yazıcı Yılmaz Yücehan, Belkaya Serkan, Timucin Emel
İhsan Doğramacı Bilkent University, Department of Molecular Biology and Genetics, Ankara 06800, Turkey.
Acibadem University, School of Medicine, Department of Biostatistics and Medical Informatics, Istanbul 34752, Turkey.
Comput Struct Biotechnol J. 2023 Jul 1;21:3522-3531. doi: 10.1016/j.csbj.2023.06.021. eCollection 2023.
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 3 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.
白细胞介素18（IL18）是一种促炎细胞因子，可调节先天性和适应性免疫反应。IL18的活性受到组成性分泌的IL18结合蛋白（IL18BP）的严格控制。人IL18的PDB结构表明，在所有IL18-IL18BP复合物中，68至81位之间的一小段氨基酸呈无序构象，而在其他IL18结构（包括受体复合物）中呈3螺旋结构。据报道，人IL18的C74在人四聚体组装中形成了一种新的分子间二硫键，它也位于这个短表位中。这些观察结果反映了这个短表面表位对IL18-IL18BP异二聚体的结构和动力学的重要性。我们通过全原子分子动力学模拟分析了PDB中所有已知的IL18-IL18BP复合物。分析还包括两个将表面表位采用螺旋结构的计算复合物模型。异二聚体模拟表明，螺旋形式的小表面区域通过降低复合物主链的灵活性对其具有稳定作用。对与对称性相关的人IL18-IL18BP四聚体的分析表明，这个小表面区域的展开也通过完全暴露的C74侧链在自组装的人IL18-IL18BP二聚体中形成分子间二硫键，从而有助于IL18-IL18BP的稳定性。我们的研究结果表明，68至81位氨基酸之间短的IL18表位的构象如何通过介导IL18的分子间相互作用来影响IL18的活性。
