A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers
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 adopte...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037023002349 |
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| author | Yılmaz Yücehan Yazıcı Serkan Belkaya Emel Timucin |
| author_facet | Yılmaz Yücehan Yazıcı Serkan Belkaya Emel Timucin |
| author_sort | Yılmaz Yücehan Yazıcı |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T21:30:18Z |
| format | Article |
| id | doaj.art-99a243f588fd496c95e01366b76c68b7 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T21:30:18Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-99a243f588fd496c95e01366b76c68b72023-12-21T07:31:43ZengElsevierComputational and Structural Biotechnology Journal2001-03702023-01-012135223531A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimersYılmaz Yücehan Yazıcı0Serkan Belkaya1Emel Timucin2İhsan Doğramacı Bilkent University, Department of Molecular Biology and Genetics, Ankara 06800, Turkeyİhsan Doğramacı Bilkent University, Department of Molecular Biology and Genetics, Ankara 06800, Turkey; Corresponding authors.Acibadem University, School of Medicine, Department of Biostatistics and Medical Informatics, Istanbul 34752, Turkey; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2001037023002349Interleukin-18Interleukin-18 binding proteinProtein-protein interactionsSelf-assemblyMolecular dynamics simulations |
| spellingShingle | Yılmaz Yücehan Yazıcı Serkan Belkaya Emel Timucin A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers Computational and Structural Biotechnology Journal Interleukin-18 Interleukin-18 binding protein Protein-protein interactions Self-assembly Molecular dynamics simulations |
| title | A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers |
| title_full | A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers |
| title_fullStr | A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers |
| title_full_unstemmed | A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers |
| title_short | A small non-interface surface epitope in human IL18 mediates the dynamics and self-assembly of IL18-IL18BP heterodimers |
| title_sort | small non interface surface epitope in human il18 mediates the dynamics and self assembly of il18 il18bp heterodimers |
| topic | Interleukin-18 Interleukin-18 binding protein Protein-protein interactions Self-assembly Molecular dynamics simulations |
| url | http://www.sciencedirect.com/science/article/pii/S2001037023002349 |
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