Investigating plasticity within the interleukin-6 family with AlphaFold-Multimer
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Stefan Düsterhöft1, Johannes N Greve2, Christoph Garbers3
1Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Cytokines are important soluble mediators that are involved in physiological and pathophysiological processes. Among them, members of the interleukin-6 (IL-6) family of cytokines have gained remarkable attention, because especially the name-giving cytokine IL-6 has been shown to be an excellent target to treat inflammatory and autoimmune diseases. The IL-6 family consists of nine members, which activate their target cells via combinations of non-signaling α- and/or signal-transducing β-receptors. While some receptor combinations are exclusively used by a single cytokine, other cytokine receptor combinations are used by multiple cytokines. Research in recent years unraveled another level of complexity: several cytokine cannot only signal via their canonical receptors, but can bind to and signal via additional α- and/or β-receptors, albeit with less affinity. While several examples of such cytokine plasticity have been reported, a systematic analysis of this phenomenon is lacking. The development of artificial intelligence programs like AlphaFold allows the computational analysis of protein complexes in a systematic manner. Here, we develop a analysis pipeline for cytokine:cytokine receptor interaction and show that AlphaFold-Multimer correctly predicts the canonical ligands of the IL-6 family. However, AlphaFold-Multimer does not provide sufficient insight to conclusively predict alternative, low-affinity ligands for receptors within the IL-6 family.
Cytokines are important soluble mediators that are involved in physiological and pathophysiological processes. Among them, members of the interleukin-6 (IL-6) family of cytokines have gained remarkable attention, because especially the name-giving cytokine IL-6 has been shown to be an excellent target to treat inflammatory and autoimmune diseases. The IL-6 family consists of nine members, which activate their target cells via combinations of non-signaling α- and/or signal-transducing β-receptors. While some receptor combinations are exclusively used by a single cytokine, other cytokine receptor combinations are used by multiple cytokines. Research in recent years unraveled another level of complexity: several cytokine cannot only signal via their canonical receptors, but can bind to and signal via additional α- and/or β-receptors, albeit with less affinity. While several examples of such cytokine plasticity have been reported, a systematic analysis of this phenomenon is lacking. The development of artificial intelligence programs like AlphaFold allows the computational analysis of protein complexes in a systematic manner. Here, we develop a analysis pipeline for cytokine:cytokine receptor interaction and show that AlphaFold-Multimer correctly predicts the canonical ligands of the IL-6 family. However, AlphaFold-Multimer does not provide sufficient insight to conclusively predict alternative, low-affinity ligands for receptors within the IL-6 family.
