Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex
Leukemia inhibitory factor (LIF) is a critical cytokine involved in various biological processes, including stem cell self-renewal, inflammation, and cancer progression. Structural studies have revealed how LIF forms a functional signaling complex. However, the dynamic binding pattern of the complex...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037025000133 |
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| author | Bo Gao Hanrui Liu Mengkai Zhu Shun Zhang Meiniang Wang Yijun Ruan Yue Zheng |
| author_facet | Bo Gao Hanrui Liu Mengkai Zhu Shun Zhang Meiniang Wang Yijun Ruan Yue Zheng |
| author_sort | Bo Gao |
| collection | DOAJ |
| description | Leukemia inhibitory factor (LIF) is a critical cytokine involved in various biological processes, including stem cell self-renewal, inflammation, and cancer progression. Structural studies have revealed how LIF forms a functional signaling complex. However, the dynamic binding pattern of the complex remains inadequately clarified. In this study, we employed molecular dynamics (MD) simulations to investigate the recognition and binding mechanisms of LIF, revealing a preferential affinity for LIF Receptor (LIFR) over gp130, attributable to a larger buried surface area at the LIF–LIFR interface. Key residues F178 and K181 in FXXK motif, along with K124 in LIF helix B, mediate hydrophobic interactions, hydrogen bonding and allosteric regulation, collectively stabilizing the LIF-LIFR interaction. We propose that the unique N-terminal extension of LIF enables signaling without requiring the additional receptor subunit beyond gp130 and LIFR, as verified by cell proliferation assays, distinguishing it from other cytokines in the LIF family. Additionally, analysis of domain fluctuations revealed that the LIF–LIFR interface undergoes less angular displacement compared to the LIF–gp130 interface, indicating a more stable interaction with LIFR. Together, these findings provide valuable insights into the molecular basis of LIF recognition and binding, offering a dynamic foundation for cytokine engineering. |
| format | Article |
| id | doaj-art-073a3c87957647db9d29000e482df7e4 |
| institution | Kabale University |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-073a3c87957647db9d29000e482df7e42025-02-06T05:11:30ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-0127585594Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complexBo Gao0Hanrui Liu1Mengkai Zhu2Shun Zhang3Meiniang Wang4Yijun Ruan5Yue Zheng6Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China; BGI Research, Hangzhou 310030, ChinaBGI Research, Changzhou 213299, ChinaBGI Research, Changzhou 213299, ChinaBGI Research, Changzhou 213299, ChinaBGI Research, Hangzhou 310030, China; Corresponding authors.Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China; Corresponding authors.BGI Research, Hangzhou 310030, China; BGI Research, Changzhou 213299, China; Corresponding author at: BGI Research, Hangzhou 310030, China.Leukemia inhibitory factor (LIF) is a critical cytokine involved in various biological processes, including stem cell self-renewal, inflammation, and cancer progression. Structural studies have revealed how LIF forms a functional signaling complex. However, the dynamic binding pattern of the complex remains inadequately clarified. In this study, we employed molecular dynamics (MD) simulations to investigate the recognition and binding mechanisms of LIF, revealing a preferential affinity for LIF Receptor (LIFR) over gp130, attributable to a larger buried surface area at the LIF–LIFR interface. Key residues F178 and K181 in FXXK motif, along with K124 in LIF helix B, mediate hydrophobic interactions, hydrogen bonding and allosteric regulation, collectively stabilizing the LIF-LIFR interaction. We propose that the unique N-terminal extension of LIF enables signaling without requiring the additional receptor subunit beyond gp130 and LIFR, as verified by cell proliferation assays, distinguishing it from other cytokines in the LIF family. Additionally, analysis of domain fluctuations revealed that the LIF–LIFR interface undergoes less angular displacement compared to the LIF–gp130 interface, indicating a more stable interaction with LIFR. Together, these findings provide valuable insights into the molecular basis of LIF recognition and binding, offering a dynamic foundation for cytokine engineering.http://www.sciencedirect.com/science/article/pii/S2001037025000133Molecular DynamicsLIFGp130LIFR |
| spellingShingle | Bo Gao Hanrui Liu Mengkai Zhu Shun Zhang Meiniang Wang Yijun Ruan Yue Zheng Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex Computational and Structural Biotechnology Journal Molecular Dynamics LIF Gp130 LIFR |
| title | Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex |
| title_full | Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex |
| title_fullStr | Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex |
| title_full_unstemmed | Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex |
| title_short | Molecular dynamics simulations reveal key roles of the LIF receptor in the assembly of human LIF signaling complex |
| title_sort | molecular dynamics simulations reveal key roles of the lif receptor in the assembly of human lif signaling complex |
| topic | Molecular Dynamics LIF Gp130 LIFR |
| url | http://www.sciencedirect.com/science/article/pii/S2001037025000133 |
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