Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
Abstract IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46235-6 |
| _version_ | 1797266724729389056 |
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| author | Scott Gardner Yibo Jin Paul K. Fyfe Tomas B. Voisin Junel Sotolongo Bellón Elizabeth Pohler Jacob Piehler Ignacio Moraga Doryen Bubeck |
| author_facet | Scott Gardner Yibo Jin Paul K. Fyfe Tomas B. Voisin Junel Sotolongo Bellón Elizabeth Pohler Jacob Piehler Ignacio Moraga Doryen Bubeck |
| author_sort | Scott Gardner |
| collection | DOAJ |
| description | Abstract IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action. |
| first_indexed | 2024-04-25T01:05:15Z |
| format | Article |
| id | doaj.art-bbc396d2171b448a8f4b408bf1d66f66 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-25T01:05:15Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-bbc396d2171b448a8f4b408bf1d66f662024-03-10T12:16:58ZengNature PortfolioNature Communications2041-17232024-03-0115111110.1038/s41467-024-46235-6Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiencyScott Gardner0Yibo Jin1Paul K. Fyfe2Tomas B. Voisin3Junel Sotolongo Bellón4Elizabeth Pohler5Jacob Piehler6Ignacio Moraga7Doryen Bubeck8Department of Life Sciences, Sir Ernst Chain Building, Imperial College LondonDepartment of Life Sciences, Sir Ernst Chain Building, Imperial College LondonDivision of Cell Signalling and Immunology, School of Life Sciences, University of DundeeDepartment of Life Sciences, Sir Ernst Chain Building, Imperial College LondonDepartment of Biology/Chemistry and Centre for Cellular Nanoanalytics, Osnabrück UniversityDivision of Cell Signalling and Immunology, School of Life Sciences, University of DundeeDepartment of Biology/Chemistry and Centre for Cellular Nanoanalytics, Osnabrück UniversityDivision of Cell Signalling and Immunology, School of Life Sciences, University of DundeeDepartment of Life Sciences, Sir Ernst Chain Building, Imperial College LondonAbstract IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.https://doi.org/10.1038/s41467-024-46235-6 |
| spellingShingle | Scott Gardner Yibo Jin Paul K. Fyfe Tomas B. Voisin Junel Sotolongo Bellón Elizabeth Pohler Jacob Piehler Ignacio Moraga Doryen Bubeck Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency Nature Communications |
| title | Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency |
| title_full | Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency |
| title_fullStr | Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency |
| title_full_unstemmed | Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency |
| title_short | Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency |
| title_sort | structural insights into il 11 mediated signalling and human il6st variant associated immunodeficiency |
| url | https://doi.org/10.1038/s41467-024-46235-6 |
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