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- Title
Heparan Sulfate Facilitates Binding of hIFN γ to Its Cell-Surface Receptor hIFNGR1.
- Authors
Miladinova, Elisaveta; Lilkova, Elena; Krachmarova, Elena; Malinova, Kristina; Petkov, Peicho; Ilieva, Nevena; Nacheva, Genoveva; Litov, Leandar
- Abstract
Human interferon-gamma (hIFN γ) 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 γ 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 γ –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 γ signalling.
- Subjects
HEPARAN sulfate; MOLECULAR dynamics; CELL membranes; SULFATION; INTERFERON gamma
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 16, p9415
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23169415