Interleukin-11 Binds Specific EF-hand Proteins via Their Conserved Structural Motifs
cancer, intrinsic disorder, interleukin, EF-hand, S100 protein, neuronal calcium sensor, protein–protein interaction
Digital Object Identifier (DOI)
Interleukin-11 (IL-11) is a hematopoietic cytokine engaged in numerous biological processes and validated as a target for treatment of various cancers. IL-11 contains intrinsically disordered regions that might recognize multiple targets. Recently we found that aside from IL-11RA and gp130 receptors, IL-11 interacts with calcium sensor protein S100P. Strict calcium dependence of this interaction suggests a possibility of IL-11 interaction with other calcium sensor proteins. Here we probed specificity of IL-11 to calcium-binding proteins of various types: calcium sensors of the EF-hand family (calmodulin, S100B and neuronal calcium sensors: recoverin, NCS-1, GCAP-1, GCAP-2), calcium buffers of the EF-hand family (S100G, oncomodulin), and a non-EF-hand calcium buffer (α-lactalbumin). A specific subset of the calcium sensor proteins (calmodulin, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants of 1–19 μM. These proteins share several amino acid residues belonging to conservative structural motifs of the EF-hand proteins, ‘black’ and ‘gray’ clusters. Replacements of the respective S100P residues by alanine drastically decrease its affinity to IL-11, suggesting their involvement into the association process. Secondary structure and accessibility of the hinge region of the EF-hand proteins studied are predicted to control specificity and selectivity of their binding to IL-11. The IL-11 interaction with the EF-hand proteins is expected to occur under numerous pathological conditions, accompanied by disintegration of plasma membrane and efflux of cellular components into the extracellular milieu.
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Citation / Publisher Attribution
Journal of Biomolecular Structure and Dynamics, v. 35, issue 1, p. 78-91
Scholar Commons Citation
Kazakov, Alexei S.; Sokolov, Andrei S.; Vologzhannikova, Alisa A.; Permyakova, Maria E.; Khorn, Polina A.; Ismailov, Ramis G.; Denessiouk, Konstantin A.; Denesyuk, Alexander I.; Rastrygina, Victoria A.; Baksheeva, Viktoriia E.; Baksheeva, Evgeni Yu.; Zinchenko, Dmitry V.; Glazatov, Vladimir V.; Uversky, Vladimir N.; Mirzabekov, Tajib A.; Permyakov, Eugene A.; and Permyakov, Sergei E., "Interleukin-11 Binds Specific EF-hand Proteins via Their Conserved Structural Motifs" (2017). Molecular Medicine Faculty Publications. 309.