Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

Abstract

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.

miR‑23b inhibits proliferation of SMMC‑7721 cells by directly targeting IL‑11

“…As a multifunctional protein, IL-11 is involved in diverse cell signaling pathways in normal cells and various pathologies ( 43 , 44 ). Its action is mediated by IL-11Rα.…”

Expression, Purification, and Characterization of Interleukin-11 Orthologues

“…Functional activities of the rIL-11 orthologues are close to or higher than those for human rIL-11, which enables their use for studies of multifaceted activity of IL-11 under normal and pathological physiological conditions, as well as for development of the drug candidates targeted against IL-11 or its receptors. The latter cover wide spectrum of oncologic, hematologic and inflammatory diseases intimately linked to IL-11 signaling [1,4,9,19]. The increased with regard to human rIL-11 ability of macaque rIL-11 to STAT3 activation and its high homology to the human protein indicate potential usefulness of macaque rIL-11 for treatment of thrombocytopenia and similar pathologic conditions requiring stimulation of hemopoiesis.…”

“…[4,17,18]), are still waiting for their translation into clinical practice. For example, IL-11 is under investigation for treatment of rheumatoid arthritis, Crohn’s disease, and other inflammatory conditions [4,9,19].…”

Single‐Particle Studies to Advance the Characterization of Heterogeneous Biocatalysts

“…All proteins, and consequently all enzymes, show intrinsic fluorescence in the UV region of the spectrum, owing to the presence of three fluorescent amino acids (tyrosine, tryptophan and phenylalanine) in their primary sequence . This strategy is mainly exploited to study protein conformational changes of the both soluble and immobilized enzymes .…”

“…All proteins, and consequently all enzymes,s how intrinsic fluorescencei nt he UV region of the spectrum, owing to the presence of three fluorescent amino acids (tyrosine, tryptophan and phenylalanine) in their primary sequence. [32] This strategyi sm ainly exploited to study protein conformational changes of the both soluble and immobilized enzymes. [33] Mappingt he proteins by recording their intrinsic fluorescence would be ideal because this techniquew ould be universal and not require anyl abeling, however, as far as we know,n onee xample hasbeen reported yet.…”