High-affinity interaction between interleukin-11 and S100P protein

Kazakov, Alexei S.; Соколов, А.С.; Rastrygina, Victoria A.; Solovyev, V. V.; Ismailov, Ramis G.; Mikhailov, Roman; Улитин, А. Б.; Yakovenko, A. R.; Mirzabekov, Tajib A.; Permyakov, Eugene A.; Permyakov, Sergei E.

doi:10.1016/j.bbrc.2015.11.024

Cited by 19 publications

(44 citation statements)

References 26 publications

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“…The 1.6-fold higher affinity of macaque rIL-11 ( K d 2 ) is in line with its 1.6-fold lower kinetic dissociation constant, k d 2 . These estimates are close to the K d (7 nM and 21.9 nM) and k d (3.5 × 10 −4 s −1 and 3.84 × 10 −3 s −1 ) values previously measured by SPR for interaction of human rIL-11, immobilized on the chip surface by amine coupling, with sIL-11Rα [32].…”

Section: Resultssupporting

confidence: 87%

“…Following this trend, we expressed macaque and murine orthologues of IL-11 as a fusion with ubiquitin (‘Ub’), instead of thioredoxin, tumor necrosis factor-α or glutathione S-transferase, used by others [27,28,29,30,31]. This approach was previously validated for preparation of human IL-11 [32]. We cloned the nucleotide sequence encoding the mature murine or macaque IL-11, which similarly to Oprelvekin lacks Pro1 residue (Table S1), into the pHUE expression vector based on pET15b [33] between the Sac II and Not I restriction sites (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…To verify this suggestion, an ability of the rIL-11 to activate Signal transducer and activator of transcription 3 (STAT3) was studied using modified HEK-Blue™ IL-6 cells line, stably transfected with human IL-11Rα gene as described in ref. [32]. The secreted embryonic alkaline phosphatase (SEAP) is liberated in response to STAT3 activation and detected using QUANTI-Blue™ colorimetric assay.…”

Section: Resultsmentioning

confidence: 99%

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Expression, Purification, and Characterization of Interleukin-11 Orthologues

et al. 2016

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Interleukin-11 (IL-11) is a multifunctional cytokine implicated in several normal and pathological processes. The decoding of IL-11 function and development of IL-11-targeted drugs dictate the use of laboratory animals and need of the better understanding of species specificity of IL-11 signaling. Here, we present a method for the recombinant interleukin-11 (rIL-11) production from the important model animals, mouse and macaque. The purified mouse and macaque rIL-11 interact with extracellular domain of human IL-11 receptor subunit α and activate STAT3 signaling in HEK293 cells co-expressing human IL-11 receptors with efficacies resembling those of human rIL-11. Hence, the evolutionary divergence does not impair IL-11 signaling. Furthermore, compared to human rIL-11 its macaque orthologue is 8-fold more effective STAT3 activator, which favors its use for treatment of thrombocytopenia as a potent substitute for human rIL-11. Compared to IL-6, IL-11 signaling exhibits lower species specificity, likely due to less conserved intrinsic disorder propensity within IL-6 orthologues. The developed express method for preparation of functionally active macaque/mouse rIL-11 samples is suited for exploration of the molecular mechanisms underlying IL-11 action and for development of the drug candidates for therapy of oncologic/hematologic/inflammatory diseases related to IL-11 signaling.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Expression, Purification, and Characterization of Interleukin-11 Orthologues

et al. 2016

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“…In agreement with these considerations, the application of the surface plasmon resonance technique revealed that aside from IL-11Ra and GP130 receptors, IL-11 interacts with calcium sensor protein S100P [45]. Recombinant forms of IL-11 and S100P interact with each other under physiological level of calcium ions.…”

Section: Interactions Of Il-11 With Calcium-binding Proteinsmentioning

confidence: 78%

“…Similarly, the release of GCAP-1/2 might occur upon autoimmune uveitis; when exposed, recoverin serves as an ocular antigen [67]. The binding of the released EFhand proteins by IL-11 could modulate its signaling in multiple ways, as previously described [45].…”

Section: Interactions Of Il-11 With Calcium-binding Proteinsmentioning

confidence: 90%

Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

Permyakov

Uversky

Permyakov

2016

Cell Biochem Biophys

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Cytokine interleukin-11 (IL-11) is a multifunctional protein with diverse roles in the normal cell signaling and in various pathologies. The structure of IL-11 is characterized by a four-helix bundle motif comprising two pairs of antiparallel α-helices arranged in an up-up-down-down configuration. Evaluation of the intrinsic disorder predisposition of human IL-11 by several computational tools clearly shows that this protein is predicted to have functional disordered regions potentially involved in interaction with natural binding partners. Signaling by IL-11 proceeds via an interaction of the protein with its membrane-specific receptor IL-11Rα and a subsequent interaction of the complex with the transmembrane signal-transducing receptor GP130. Cytoplasmic domain of IL-11Rα is predicted to be very disordered, and noticeable amount of disorder is present even in the large extracellular domain of the protein. GP130 is also predicted to have long disordered region that is located at the C-terminal of the protein and is expected to have several disorder-based binding sites. It shows that intrinsic disorder might play an important role in functioning of this signaling machine. A specific subset of the calcium sensor proteins (calmodulin, S100P, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants in a range of 1-19 μM, and the structural features of their hinge regions likely ensure selectivity and calcium sensitivity of IL-11 binding to the EF-hand proteins studied. IL-11 exhibits multiple effects on hematopoietic and non-hematopoietic systems. It plays a major role in orchestrating complex processes of tumor development and progression.

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