Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.

Area of Science:

• Biochemistry
• Structural Biology
• Cell Signaling

Background:

• Homodimeric class 1 cytokine receptors (e.g., EPOR, TPOR, CSF3R, GHR, PRLR) are single-pass transmembrane glycoproteins regulating crucial cellular processes.
• These receptors, when activated, form signaling complexes with ligands and Janus Kinase 2 (JAK2), but their complete structure and dynamics remain poorly understood.
• Understanding these complexes is vital for deciphering cell growth, differentiation, and oncogenesis.

Purpose of the Study:

• To generate three-dimensional models of five human homodimeric class 1 cytokine receptor complexes with ligands and JAK2.
• To elucidate the structural basis of receptor activation and the JAK-STAT signaling pathway.
• To investigate the molecular mechanisms of oncogenic mutations in these receptors.

Main Methods:

• Utilized AlphaFold Multimer for stepwise modeling of large receptor-cytokine-JAK2 complexes (3220–4074 residues).
• Validated models by comparing with existing experimental data.
• Performed molecular dynamics simulations of complexes within explicit plasma membrane lipids.

Main Results:

• Developed models for active and inactive states of five human homodimeric class 1 cytokine receptor complexes.
• Proposed a general activation mechanism involving ligand-induced receptor dimerization and TM α-helix rotation, leading to JAK2 activation.
• Modeled eltrombopag binding to thrombopoietin receptor (TPOR) and provided insights into oncogenic mutations.

Conclusions:

• The generated models provide a structural framework for understanding class 1 cytokine receptor activation and JAK-STAT signaling.
• These models offer molecular insights into oncogenesis driven by these receptors.
• The computational models are publicly available for further research.