Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1
Human interferon-gamma (hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>) is a crucial signaling molecule with an important role in the i...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9415 |
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| author | Elisaveta Miladinova Elena Lilkova Elena Krachmarova Kristina Malinova Peicho Petkov Nevena Ilieva Genoveva Nacheva Leandar Litov |
| author_facet | Elisaveta Miladinova Elena Lilkova Elena Krachmarova Kristina Malinova Peicho Petkov Nevena Ilieva Genoveva Nacheva Leandar Litov |
| author_sort | Elisaveta Miladinova |
| collection | DOAJ |
| description | Human interferon-gamma (hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula> to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>–hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula> signalling. |
| first_indexed | 2024-03-09T13:14:57Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T13:14:57Z |
| publishDate | 2022-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d8369db82c154ed3b5485bb89fef30df2023-11-30T21:37:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316941510.3390/ijms23169415Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1Elisaveta Miladinova0Elena Lilkova1Elena Krachmarova2Kristina Malinova3Peicho Petkov4Nevena Ilieva5Genoveva Nacheva6Leandar Litov7Faculty of Physics, Sofia University “St. Kliment Ohridski”, 5 James Bourchier Blvd., 1164 Sofia, BulgariaInstitute of Information and Communication Technologies, Bulgarian Academy of Sciences, 2 Acad. G. Bonchev Str., 1113 Sofia, BulgariaInstitute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, 21 Acad. G. Bonchev Str., 1113 Sofia, BulgariaInstitute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, 21 Acad. G. Bonchev Str., 1113 Sofia, BulgariaFaculty of Physics, Sofia University “St. Kliment Ohridski”, 5 James Bourchier Blvd., 1164 Sofia, BulgariaInstitute of Information and Communication Technologies, Bulgarian Academy of Sciences, 2 Acad. G. Bonchev Str., 1113 Sofia, BulgariaInstitute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, 21 Acad. G. Bonchev Str., 1113 Sofia, BulgariaFaculty of Physics, Sofia University “St. Kliment Ohridski”, 5 James Bourchier Blvd., 1164 Sofia, BulgariaHuman interferon-gamma (hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>) is a crucial signaling molecule with an important role in the initialization and development of the immune response of the host. However, its aberrant activity is also associated with the progression of a multitude of autoimmune and other diseases, which determines the need for effective inhibitors of its activity. The development of such treatments requires proper understanding of the interaction of hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula> to its cell-surface receptor hIFNGR1. Currently, there is no comprehensive model of the mechanism of this binding process. Here, we employ molecular dynamics simulations to study on a microscopic level the process of hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula>–hIFNGR1 complex formation in different scenarios. We find that the two molecules alone fail to form a stable complex, but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity assay on cells depleted from cell-surface heparan sulfate (HS) sulfation together with the phosphorylation levels of the signal transducer and activator of transcription STAT1 confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFN<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>γ</mi></semantics></math></inline-formula> signalling.https://www.mdpi.com/1422-0067/23/16/9415human interferon gammahuman interferon gamma receptorheparan sulfatemolecular dynamics simulationssodium chlorate |
| spellingShingle | Elisaveta Miladinova Elena Lilkova Elena Krachmarova Kristina Malinova Peicho Petkov Nevena Ilieva Genoveva Nacheva Leandar Litov Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 International Journal of Molecular Sciences human interferon gamma human interferon gamma receptor heparan sulfate molecular dynamics simulations sodium chlorate |
| title | Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 |
| title_full | Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 |
| title_fullStr | Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 |
| title_full_unstemmed | Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 |
| title_short | Heparan Sulfate Facilitates Binding of hIFN<i>γ</i> to Its Cell-Surface Receptor hIFNGR1 |
| title_sort | heparan sulfate facilitates binding of hifn i γ i to its cell surface receptor hifngr1 |
| topic | human interferon gamma human interferon gamma receptor heparan sulfate molecular dynamics simulations sodium chlorate |
| url | https://www.mdpi.com/1422-0067/23/16/9415 |
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