A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor α chain

Wang, Yonghong; Shen, Bo; Sebald, Walter

doi:10.1073/pnas.94.5.1657

Cited by 84 publications

(78 citation statements)

References 38 publications

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“…Similar electrostatic interactions have been described in the human GM-CSF-receptor complex (33,34) and the IL-4⅐IL-4 receptor ␣ chain complex (35). Arg 280 in the ␣-chain of the GM-CSF-R makes an electrostatic interaction with Asp 112 in the D helix of GM-CSF (33), whereas Glu 21 in the A helix probably interacts with Tyr 365 , His 367 , and Ile 368 of the ␤-common receptor chain (34).…”

Section: Discussionmentioning

confidence: 63%

“…Arg 280 in the ␣-chain of the GM-CSF-R makes an electrostatic interaction with Asp 112 in the D helix of GM-CSF (33), whereas Glu 21 in the A helix probably interacts with Tyr 365 , His 367 , and Ile 368 of the ␤-common receptor chain (34). IL-4 binding to the IL-4 receptor ␣ chain involves a patch of charged residues on the A and C helices that is likely to interact with charged residues on the receptor (35). In other cases such as the growth hormonereceptor complex, the most important interactions are hydrophobic (36).…”

Section: Discussionmentioning

confidence: 99%

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Interaction of Granulocyte Colony-stimulating Factor (G-CSF) with Its Receptor

Layton

Shimamoto²,

Osslund³

et al. 1999

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Interaction of Granulocyte Colony-stimulating Factor (G-CSF) with Its Receptor

Layton

Shimamoto²,

Osslund³

et al. 1999

Journal of Biological Chemistry

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“…9 Direct experiments in the BIAcore system have revealed that the normally glycosylated mIL-4 directly binds to hIL-4 receptor a (Ra). 9 Moreover, several previous reports have shown that hIL-4 is active in mice or rats in vivo in a fashion similar to that of mIL-4. [10][11][12] It is therefore possible that hIL-4 may be at least partially active in vivo in mice.…”

Section: Discussionmentioning

confidence: 99%

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Summary Interleukin‐4 (IL‐4) acts on cultured cells in a species‐specific fashion, although several reports have suggested that human (h) IL‐4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre‐clinical testing of novel hIL‐4‐targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL‐4 and its receptors. Conventional IL‐4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL‐4δ2). Replication‐deficient adenovirus‐mediated gene delivery of hIL‐4 isoforms (hIL‐4 or hIL‐4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL‐4 compared with hIL‐4δ2, with hIL‐4δ2 inducing higher levels of pro‐inflammatory (tumour necrosis factor‐α, IL‐1, and monocyte chemotactic protein‐1) and T helper type 1 (IL‐12 and interferon‐γ) cytokines. There was no elevation in endogenous mouse (m) IL‐4 or mIL‐4δ2 mRNAs, and germ‐line deficiency of mIL‐4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL‐4δ2 stimulated a greater accumulation of lymphocytes than did hIL‐4. Pulmonary infiltration of lymphocytes induced by expression of hIL‐4 or hIL‐4δ2 was attenuated, but not completely abrogated, by germ‐line deficiency of mIL‐4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL‐4 isoforms in mice. These findings suggest that splice isoforms of human IL‐4 are functionally active in vivo in mice, and partially share the effects of the corresponding species‐specific isoforms.

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“…Many biological processes rely on the rapid formation of protein-ligand complexes (1)(2)(3)(4)(5). Consequently, there has been great interest in elucidating the mechanisms through which binding partners are able to efficiently recognize each other in solution and adopt the correct conformations, relative positions, and orientations to form native stereo-specific complexes.…”

mentioning

confidence: 99%

Electrostatic Interactions in the Binding Pathway of a Transient Protein Complex Studied by NMR and Isothermal Titration Calorimetry

Meneses

Mittermaier

2014

Journal of Biological Chemistry

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Background: Electrostatic interactions are known accelerate binding in protein complexes with long lifetimes (minutes to hours). Results: NMR and calorimetry were used to characterize binding kinetics in short lived (ϳ1 ms) protein-peptide complexes. Conclusion: Electrostatic enhancement is much less and basal (electrostatic-free) association rates are greater than previously observed. Significance: Electrostatics may play different roles in short lived and long lived protein complexes.

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A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor α chain

Abstract: Human interleukin 4 (IL-4) binds to its

Cited by 84 publications

References 38 publications

Interaction of Granulocyte Colony-stimulating Factor (G-CSF) with Its Receptor

Interaction of Granulocyte Colony-stimulating Factor (G-CSF) with Its Receptor

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Electrostatic Interactions in the Binding Pathway of a Transient Protein Complex Studied by NMR and Isothermal Titration Calorimetry

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