The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities.

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon.

Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

Background: The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.

Methods: We performed a high-throughput, combination chromatin-modifier drug screen against NB cells.

Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

Background: CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor).

Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions.

Human 5'-3' exonuclease PLD3, a member of the phospholipase D family of enzymes, has been validated as a therapeutic target for treating Alzheimer's disease. Here, we have determined the crystal structure of the luminal domain of the enzyme at 2.3 Å resolution, revealing a bilobal structure with a catalytic site located between the lobes.

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Unlabelled: Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation.

A novel phosphocholine-mimetic inhibits a pro-inflammatory conformational change in C-reactive protein.

C-reactive protein (CRP) is an early-stage acute phase protein and highly upregulated in response to inflammatory reactions. We recently identified a novel mechanism that leads to a conformational change from the native, functionally relatively inert, pentameric CRP (pCRP) structure to a pentameric CRP intermediate (pCRP*) and ultimately to the monomeric CRP (mCRP) form, both exhibiting highly pro-inflammatory effects. This transition in the inflammatory profile of CRP is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine lipid head groups.

C-reactive protein, immunothrombosis and venous thromboembolism.

C-reactive protein (CRP) is a member of the highly conserved pentraxin superfamily of proteins and is often used in clinical practice as a marker of infection and inflammation. There is now increasing evidence that CRP is not only a marker of inflammation, but also that destabilized isoforms of CRP possess pro-inflammatory and pro-thrombotic properties. CRP circulates as a functionally inert pentameric form (pCRP), which relaxes its conformation to pCRP* after binding to phosphocholine-enriched membranes and then dissociates to monomeric CRP (mCRP).

Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia.

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown.

Structural biology of cell surface receptors implicated in Alzheimer's disease.

Alzheimer's disease is a common and devastating age-related disease with no effective disease-modifying treatments. Human genetics has implicated a wide range of cell surface receptors as playing a role in the disease, many of which are involved in the production or clearance of neurotoxins in the brain. Amyloid precursor protein, a membrane-bound signaling molecule, is at the very heart of the disease: hereditary mutations in its gene are associated with a greatly increased risk of getting the disease.

Transitional changes in the structure of C-reactive protein create highly pro-inflammatory molecules: Therapeutic implications for cardiovascular diseases.

C-reactive protein (CRP) is the prototypic acute-phase reactant that has long been recognized almost exclusively as a marker of inflammation and predictor of cardiovascular risk. However, accumulating evidence indicates that CRP is also a direct pathogenic pro-inflammatory mediator in atherosclerosis and cardiovascular diseases. The 'CRP system' consists of at least two protein conformations with distinct pathophysiological functions.

Messing with βc: A unique receptor with many goals.

Our understanding of the biological role of the βc family of cytokines has evolved enormously since their initial identification as bone marrow colony stimulating factors in the 1960's. It has become abundantly clear over the intervening decades that this family of cytokines has truly astonishing pleiotropic capacity, capable of regulating not only hematopoiesis but also many other normal and pathological processes such as development, inflammation, allergy and cancer. As noted in the current pandemic, βc cytokines contribute to the cytokine storm seen in acutely ill COVID-19 patients.

Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms.

Long-chain fatty acids (LCFAs) play important roles in cellular energy metabolism, acting as both an important energy source and signalling molecules. LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation. Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase.

Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments.

G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cellular membrane receptors identified and characterized. It is estimated that 30 to 50% of marketed drugs target these receptors. The angiotensin II receptor type 1 (AT1R) is a GPCR which signals in response to systemic alterations of the peptide hormone angiotensin II (AngII) in circulation.

Repurposing of drugs as STAT3 inhibitors for cancer therapy.

Drug repurposing is a valuable approach in delivering new cancer therapeutics rapidly into the clinic. Existing safety and patient tolerability data for drugs already in clinical use represent an untapped resource in terms of identifying therapeutic agents for off-label protein targets. The multicellular effects of STAT3 mediated by a range of various upstream signaling pathways make it an attractive therapeutic target with utility in a range of diseases including cancer, and has led to the development of a variety of STAT3 inhibitors.

A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites.

Parasitic protists belonging to the genus Leishmania synthesize the non-canonical carbohydrate reserve, mannogen, which is composed of β-1,2-mannan oligosaccharides. Here, we identify a class of dual-activity mannosyltransferase/phosphorylases (MTPs) that catalyze both the sugar nucleotide-dependent biosynthesis and phosphorolytic turnover of mannogen. Structural and phylogenic analysis shows that while the MTPs are structurally related to bacterial mannan phosphorylases, they constitute a distinct family of glycosyltransferases (GT108) that have likely been acquired by horizontal gene transfer from gram-positive bacteria.

Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis.

Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure.

Author Correction: EPO does not promote interaction between the erythropoietin and beta-common receptors.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Repurposing the selective estrogen receptor modulator to suppress gastrointestinal cancer growth.

Excessive signaling through gp130, the shared receptor for the interleukin (IL)6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the utility of a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130-dependent tumor growth of the gastrointestinal epithelium. administration reduced gastric tumor burden in mice, where tumors arise exclusively through excessive gp130/STAT3 signaling in response to the IL6 family cytokine IL11.

Protein structure and computational drug discovery.

The first protein structures revealed a complex web of weak interactions stabilising the three-dimensional shape of the molecule. Small molecule ligands were then found to exploit these same weak binding events to modulate protein function or act as substrates in enzymatic reactions. As the understanding of ligand-protein binding grew, it became possible to firstly predict how and where a particular small molecule might interact with a protein, and then to identify putative ligands for a specific protein site.

EPO does not promote interaction between the erythropoietin and beta-common receptors.

A direct interaction between the erythropoietin (EPOR) and the beta-common (βc) receptors to form an Innate Repair Receptor (IRR) is controversial. On one hand, studies have shown a functional link between EPOR and βc receptor in tissue protection while others have shown no involvement of the βc receptor in tissue repair. To date there is no biophysical evidence to confirm a direct association of the two receptors either in vitro or in vivo.

The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that can stimulate a variety of cells, but its overexpression leads to excessive production and activation of granulocytes and macrophages with many pathogenic effects. This cytokine is a therapeutic target in inflammatory diseases, and several anti-GM-CSF antibodies have advanced to Phase 2 clinical trials in patients with such diseases, e.g.

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling.

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W.

Role of the β Common (βc) Family of Cytokines in Health and Disease.

The β common ([βc]/CD131) family of cytokines comprises granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5, all of which use βc as their key signaling receptor subunit. This is a prototypic signaling subunit-sharing cytokine family that has unveiled many biological paradigms and structural principles applicable to the IL-2, IL-4, and IL-6 receptor families, all of which also share one or more signaling subunits. Originally identified for their functions in the hematopoietic system, the βc cytokines are now known to be truly pleiotropic, impacting on multiple cell types, organs, and biological systems, and thereby controlling the balance between health and disease.