Conformational Changes in the GM-CSF Receptor Suggest a Molecular Mechanism for Affinity Conversion and Receptor Signaling

Broughton, Sophie E.; Hercus, Timothy R.; Nero, Tracy L.; Dottore, Mara; McClure, Barbara J.; Dhagat, Urmi; Taing, Houng; Gorman, Michael A.; King-Scott, J.; Lopez, Angel F.; Parker, Michael W.

doi:10.1016/j.str.2016.05.017

Cited by 41 publications

(68 citation statements)

References 36 publications

(86 reference statements)

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“…[10]), as well as cytokine receptor interactions, in particular studies of type I interferons also from the Schreiber group (e.g. [63]) and that of K. Christopher Garcia [70], but also the study of the GM-CSF / GMRα interaction from the group of Michael W. Parker [9]. Other prominent sources of data are studies into hormone receptor interactions, in particular the human growth hormone receptor from the group of Jim Wells (e.g.…”

Section: B Notable Studies Comprising Skempi 20mentioning

confidence: 99%

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

Jankauskaite

Jiménez‐García

Dapkūnas

et al. 2018

Preprint

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Motivation: Understanding the relationship between the sequence, structure, binding energy, binding kinetics and binding thermodynamics of protein-protein interactions is crucial to understanding cellular signaling, the assembly and regulation of molecular complexes, the mechanisms through which mutations lead to disease, and protein engineering. Results: We present SKEMPI 2.0, a major update to our database of binding free energy changes upon mutation for structurally resolved protein-protein interactions. This version now contains manually curated binding data for 7085 mutations, an increase of 133%, including changes in kinetics for 1844 mutations, enthalpy and entropy changes for 443 mutations, and 440 mutations which abolish detectable binding. Availability:The database is available at

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Section: B Notable Studies Comprising Skempi 20mentioning

confidence: 99%

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

Jankauskaite

Jiménez‐García

Dapkūnas

et al. 2018

Preprint

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“…82 The dodecamer formation provides a conformational structure that moves the central intracellular βc domains into close proximity (~10 Å versus ~120 Å in the hexamer formation) to enable JAK2 transphosphorylation and initiation of the JAK2/STAT5 signaling pathway. 82, 83 …”

Section: The Common Beta-chain Cytokine Receptorsmentioning

confidence: 99%

Essential mechanisms of differential activation of eosinophils by IL-3 compared to GM-CSF and IL-5

Esnault

Kelly

2017

Crit Rev Immunol

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There is compelling evidence that the eosinophils bring negative biological outcomes in several diseases, including eosinophilic asthma and hypereosinophilic syndromes. Eosinophils produce and store a broad range of toxic proteins and other mediators that enhance the inflammatory response and lead to tissue damage. For instance, in asthma, there is a close relationship between increased lung eosinophilia, asthma exacerbation, and loss of lung function. The use of an anti-IL-5 therapy in severe eosinophilic asthmatic patients is efficient to reduce exacerbations. However, anti-IL-5-treated patients still display a relatively high amount of functional lung tissue eosinophils, indicating that supplemental therapies are required to damper the eosinophil functions. Our recent published works, suggest that compared to IL-5, IL-3 can more strongly and differentially affect eosinophil functions. In this review, we will summarize our and other investigations that have compared the effects of the three β-chain receptor cytokines (IL-5, GM-CSF and IL-3) on eosinophil biology. We will focus on how IL-3 differentially activates eosinophils compared to IL-5 or GM-CSF.

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“…5e,f) and in light of the GIF-mediated abrogation of the bioactivity of the two cytokines in cellular assays20, we sought to trace the structural basis for the antagonistic properties of GIF. In the first instance we compared the binding mode of ovine GM-CSF to GIF with the structure of human GM-CSF in complex with its cognate receptors GMRα and βc (refs 32, 33). The two GM-CSF orthologues share 80% sequence identity and can be superposed with an r.m.s.d.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

et al. 2016

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Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses.

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Conformational Changes in the GM-CSF Receptor Suggest a Molecular Mechanism for Affinity Conversion and Receptor Signaling

Cited by 41 publications

References 36 publications

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

Essential mechanisms of differential activation of eosinophils by IL-3 compared to GM-CSF and IL-5

Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

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