2l3o
Solution structure of murine interleukin 3
Structural highlights
FunctionIL3_MOUSE Cytokine secreted predominantly by activated T-lymphocytes as well as mast cells and osteoblastic cells that controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells. Stimulates also mature basophils, eosinophils, and monocytes to become functionally activated. In addition, plays an important role in neural cell proliferation and survival. Participates as well in bone homeostasis and inhibits osteoclast differentiation by preventing NF-kappa-B nuclear translocation and activation. Mechanistically, exerts its biological effects through a receptor composed of IL3RA subunit and a signal transducing subunit IL3RB (By similarity). Receptor stimulation results in the rapid activation of JAK2 kinase activity leading to STAT5-mediated transcriptional program (PubMed:10376805, PubMed:31990690, PubMed:8378315). Alternatively, contributes to cell survival under oxidative stress in non-hematopoietic systems by activating pathways mediated by PI3K/AKT and ERK (By similarity).[UniProtKB:P08700][1] [2] [3] [4] Publication Abstract from PubMedInterleukin-3 (IL-3), a cytokine produced primarily by activated T-cells during immune responses, is a crucial regulator of allergic inflammation. The three-dimensional structure of murine IL-3 (mIL-3) has remained elusive owing to its poor solubility and strong tendency toward aggregation under solution conditions typically used for structural studies. Here we describe the solution properties and structure of mIL-3 determined by NMR using an engineered construct of mIL-3 (mIL-3(33-156)). mIL-3 adopts a four-helical bundle fold, typical of proteins belonging to the short-chain cytokine family, and features a core of highly conserved hydrophobic residues. While significant line broadening and peak disappearance were observed in NMR spectra at higher temperatures, there was no evidence for temperature-dependent changes of the oligomeric state of mIL-3(33-156). Further analysis of the temperature dependence of amide (1)H chemical shifts and backbone (15)N relaxation parameters, including (15)N relaxation dispersion, revealed the presence of significant conformational exchange and local conformational heterogeneity. Residues recently shown by mutagenesis to play key roles in beta(IL-3) receptor recognition and activation, which are located within the alpha(A) and alpha(C) helices and aligned on one face of the mIL-3(33-156) structure, are relatively rigid. In contrast, pronounced conformational heterogeneity was observed for a cluster of residues located on the opposite side of mIL-3, which corresponds spatially to sites in the related cytokines human IL-3, IL-5, and GM-CSF that are known to mediate interactions with their respective alpha-receptor subunits. Such conformational heterogeneity may facilitate the interaction of mIL-3 with each of two naturally occurring mIL-3Ralpha isoforms, leading to structurally distinct high-affinity complexes. Murine interleukin-3: structure, dynamics, and conformational heterogeneity in solution.,Yao S, Young IG, Norton RS, Murphy JM Biochemistry. 2011 Apr 5;50(13):2464-77. Epub 2011 Mar 2. PMID:21329364[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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