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Comparison of the 3D models of four different human IL-7 isoforms with human and murine IL-7
R T Kroemer1, R Kröncke, J Gerdes
1Physical and Theoretical Chemistry Laboratory, University of Oxford, UK.
Abstract:
The three-dimensional (3D) models of several alternatively spliced isoforms (ISO1 through ISO4) of human interleukin-7 (hIL-7) are presented. They are based on sequences of mRNA recently discovered in follicular dendritic cells (FDC) and primary cultures of endothelial cells or smooth muscle cells. The structures were docked to a previous model of the human IL-7 receptor, containing the IL-7 specific (IL-7R) and common gamma (gamma(c)) chain. Two different models of murine IL-7 (mIL-7) were generated as well and docked to this receptor. For an evaluation of the structures and the possible biological role of the isoforms, the models were analysed in detail and a series of enthalpy calculations was carried out. Compared with hIL-7, ISO1 appears to bind equally well to hIL-7R, but even better to the gamma(c) chain. This suggests an agonist role of ISO1, which has already been shown experimentally. The prediction that ISO2 exhibits reduced affinity to hIL-7R is supported by experiments where it had been shown to be inactive in a human test system. However, ISO2 as well as ISO3 could represent antagonists for hIL-7. Remarkably, mIL-7 appears to bind significantly less well to hIL-7R, which is in line with experimental observations that it is not active in the human system. The sequences of the isoforms support the helix assignment made for the previous hIL-7 model.
Insights
New 3D models of human interleukin-7 (hIL-7) isoforms reveal distinct binding properties. These findings explain the biological roles of hIL-7 variants and mouse IL-7 (mIL-7) interactions with the IL-7 receptor.
Area of Science:
- Structural biology
- Immunology
- Molecular modeling
Background:
- Interleukin-7 (IL-7) is crucial for lymphocyte development and function.
- Alternative splicing of IL-7 mRNA generates various isoforms with potentially distinct biological activities.
- Understanding IL-7 isoform structure-function relationships is key to deciphering immune regulation.
Purpose of the Study:
- To generate and analyze three-dimensional (3D) models of human IL-7 (hIL-7) isoforms (ISO1-ISO4).
- To investigate the binding interactions of hIL-7 isoforms and murine IL-7 (mIL-7) with the human IL-7 receptor (hIL-7R) complex.
- To predict the functional roles of different hIL-7 isoforms based on their structural models.
Main Methods:
- Development of 3D structural models for four hIL-7 isoforms based on newly discovered mRNA sequences.
- Docking of hIL-7 isoform models and two mIL-7 models to a previously established human IL-7 receptor model (comprising IL-7R and gamma(c) chain).
- Detailed analysis of structural models and enthalpy calculations to evaluate binding affinities and predict biological activity.
Main Results:
- hIL-7 ISO1 demonstrates strong binding to both hIL-7R and gamma(c) chain, supporting its known agonist activity.
- ISO2 and ISO3 show potential antagonist roles for hIL-7, with ISO2 exhibiting reduced affinity to hIL-7R, consistent with experimental data.
- Murine IL-7 (mIL-7) exhibits significantly weaker binding to hIL-7R, explaining its lack of activity in human systems.
Conclusions:
- The generated 3D models provide insights into the differential binding capabilities of hIL-7 isoforms.
- Structural predictions align with experimental observations regarding the activity and interactions of hIL-7 and mIL-7.
- These models contribute to understanding the complex roles of IL-7 isoforms in immune responses.