Naturally occurring and synthetic constitutive-active cytokine receptors in disease and therapy

Floß, Doreen M.; Scheller, Jürgen

doi:10.1016/j.cytogfr.2019.05.007

Cited by 13 publications

(14 citation statements)

References 239 publications

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“…The latter usually cause the constitutive activation of cytokine receptors and JAK kinases. 10,43,94 Mapping of known oncogenic missense mutations onto the AFM-based models of active ligandreceptor-kinase complexes may shed light on possible molecular mechanisms of pathological effects of these mutations.…”

Section: Afm-generated Structures Of Signaling Complexes Of Homodimer...mentioning

confidence: 99%

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer

Pogozheva,

Cherepanov,

Park

et al. 2023

J. Chem. Inf. Model.

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Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). These cell-surface single-pass transmembrane (TM) glycoproteins regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains, and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all of the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated here by using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts, with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices, causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to the TM α-helices of the active TPOR dimer was proposed. The models also help elucidate the molecular basis of oncogenic mutations that may involve a noncanonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.

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Section: Afm-generated Structures Of Signaling Complexes Of Homodimer...mentioning

confidence: 99%

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer

Pogozheva,

Cherepanov,

Park

et al. 2023

J. Chem. Inf. Model.

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“…Receptor dimers are fundamentally required for JAK activation 60, 61 but higher order stoichiometry such as tetrameric receptors comprising two pairs of JAKs are also found in the class I and II receptor families. Recent experimental advances in multicolor single-molecule imaging have enabled to quantify receptor stoichiometries of signaling complexes in the plasma membrane of live cells 62 .…”

Section: Mainmentioning

confidence: 99%

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

Tsirigotaki

Dansercoer

Verschueren

et al. 2022

Preprint

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The adipokine Leptin activates its type I cytokine receptor (LEP-R) in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility, and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Here, we show that Leptin:LEP-R assemblies adopt an unprecedented structure within the type I cytokine receptor family featuring 3:3 stoichiometry. We validate Leptin-induced trimerization of LEP-R in the plasma membrane of living cells via multicolor single molecule microscopy. In mediating such assemblies Leptin undergoes drastic restructuring that activates its site III for binding to the Ig-domain of an adjacent LEP-R molecule in the complex. These interactions are abolished by pathological mutations linked to obesity. Collectively, our study uncovers an evolutionarily conserved Leptin:LEP-R assembly as a new mechanistic blueprint for Leptin-mediated signaling in physiology and disease, including insights into how the lowly abundant signaling-competent isoforms of LEP-R can productively participate in signaling.

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“…The simulation of this phenomenon, together with a theoretical analysis of absorption process based on Markov models, allows dimensioning the detection process through receptors having the properties to bind with IL-6 cytokines. Examples of synthetic receptors able to absorb cytokines and further transmit biological signals are shown in [8] and [9] . Furthermore, having the possibility to numerically evaluate the reception process at the receiver site, it is also possible to evaluate the concentration of antibodies necessary to effectively counteract the inflammatory process by occupying IL-6R receptors exposed by the endothelium.…”

Section: Introductionmentioning

confidence: 99%

A Molecular Communications System for the Detection of Inflammatory Levels Related to COVID-19 Disease

Felicetti

Femminella

Reali

2021

IEEE Trans. Mol. Biol. Multi-Scale Commun.

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A recent and extensive research activity highlighted the process behind the attack and spread of COVID-19 in the human body. What emerged is that the SARS-CoV-2 virus makes use of both the ACE2 receptor, expressed by pneumocytes in the ephitelial alveolar lining, and by the endothelium to spread the disease and to replicate itself. Since the endothelium is an extended tissue lying in the circulatory system, this may lead to a large state of diffuse endothelial inflammation with serious clinical consequences. This situation may be further compromised by the immune system, that may generate pro-inflammatory cytokines (IL-6) as a consequence of the infection. In this paper we propose and analyze a molecular communication system, designed for the detection of excessive IL-6 level, that allows monitoring its evolution in the blood vessels. The proposed analysis was performed by using the BiNS2 simulator, which is suitable for the numerical analysis of flow-based molecular communications in blood vessels, as well as Markov models of the endothelium.

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Naturally occurring and synthetic constitutive-active cytokine receptors in disease and therapy

Cited by 13 publications

References 239 publications

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer

Mechanism of receptor assembly via the pleiotropic adipokine Leptin

A Molecular Communications System for the Detection of Inflammatory Levels Related to COVID-19 Disease

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