Human and Mouse CD137 Have Predominantly Different Binding CRDs to Their Respective Ligands

Yi, Ling; Zhao, Yanlin; Wang, Xiaojue; Dai, Min; Hellström, Karl Erik; Hellström, Ingegerd; Zhang, Hongtao

doi:10.1371/journal.pone.0086337

Cited by 13 publications

(20 citation statements)

References 42 publications

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“…However, deletion of the first or second CRD diminished binding of 4-1BB-Fc to 4-1BBL (Supporting Information Fig. 1B), corresponding to a previous study also showed that both the first and second CRD are essential for the binding of 4-1BB-Fc to 4-1BBL [19]. We further evaluated the inhibitory activities of 4-1BB-Fc mutant molecules on sustained TNF production in vitro.…”

Section: Analysis Of Binding Activity Of 4-1bb-fc To 4-1bblsupporting

confidence: 71%

Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice

et al. 2015

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Activation of Toll-like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is sustained for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4-1BB ligand (4-1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4-1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin-induced sepsis in mice. A 4-1BB-Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4-1BBL. Administration of 4-1BB-Fc suppressed LPS-induced sepsis by reducing TNF production, and the co-administration of anti-TNF and 4-1BB-Fc provided more protection against LPS-induced sepsis. Therefore, these observations suggest that inhibition of the TLR/4-1BBL complex formation may be highly efficacious in protecting against sustained inflammation, and that 4-1BB-Fc treatment may be a potential therapeutic option for inflammatory diseases.

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Section: Analysis Of Binding Activity Of 4-1bb-fc To 4-1bblsupporting

confidence: 71%

Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice

et al. 2015

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“…In contrast, 4-1BB/4-1BBL interactions are largely species-specific. Although h4-1BB does not bind to m4-1BBL, m4-1BB binds to h4-1BBL with greatly reduced affinity compared with that of h4-1BB (22). To understand the greatly restricted cross-species interactions, we compared the overall architecture of the respective 4-1BB/4-1BBL complexes (Fig.…”

Section: Comparison With the H4-1bb/4-1bbl Complexmentioning

confidence: 99%

Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding

Bitra

Doukov

Destito

et al. 2019

Journal of Biological Chemistry

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Edited by Peter CresswellThe interaction between the receptor 4-1BB and its ligand 4-1BBL provides co-stimulatory signals for T-cell activation and proliferation. However, differences in the mouse and human molecules might result in differential engagement of this pathway. Here, we report the crystal structure of mouse 4-1BBL and of the mouse 4-1BB/4-1BBL complex, which together provided insights into the molecular mechanism by which m4-1BBL and its cognate receptor recognize each other. Unlike all human or mouse tumor necrosis factor ligands that form noncovalent and mostly trimeric assemblies, the m4-1BBL structure formed a disulfide-linked dimeric assembly. The structure disclosed that certain differences in the amino acid composition along the intramolecular interface, together with two specific residues (Cys-246 and Ser-256) present exclusively in m4-1BBL, are responsible for this unique dimerization. Unexpectedly, upon m4-1BB binding, m4-1BBL undergoes structural changes within each protomer; moreover, the individual m4-1BBL protomers rotate relative to each other, yielding a dimerization interface with more inter-subunit interactions. We also observed that in the m4-1BB/4-1BBL complex, each receptor monomer binds exclusively to a single ligand subunit with contributions of cysteine-rich domain 1 (CRD1), CRD2, and CRD3. Furthermore, structure-guided mutagenesis of the binding interface revealed that novel binding interactions with the GH loop, rather than the DE loop, are energetically critical and define the m4-1BB receptor selectivity for m4-1BBL. A comparison with the human 4-1BB/4-1BBL complex highlighted several differences between the ligand-and receptorbinding interfaces, providing an explanation for the absence of inter-species cross-reactivity between human and mouse 4-1BB and 4-1BBL molecules.

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“…Full-length SPLUNC1 cDNA was amplified by PCR and cloned into PCDM-L and PCDH-L, (13) which included the fragment of mouse IgG-Fc (mFc) and human IgG-Fc (hFc), respectively. The primers for the construction of PCDH-L-SPLUNC1 were: 5¢-CGCAAGCTTCAGATACTAAGAGC AAAGATG-3¢ and 5¢-CGCAGATCTGACCTTGATGACA AACTGTAG-3¢.…”

Section: Production Of Fusion Proteinmentioning

confidence: 99%

“…The purity of the fusion protein was confirmed by spectrophotometer (UV-2550, Shimadzu, Kyoto, Japan) and SDS-PAGE gel electrophoresis. A control fusion protein mE3-hFc, which was mouse CD137 cysteine-rich domains with human IgG-Fc, was produced by our laboratory, (13) and another control of human IgG1-Fc protein was purchased from Sino Biological (Beijing, China).…”

Section: Production Of Fusion Proteinmentioning

confidence: 99%

“…(14) Briefly, microtiter polystyrene plates were separately coated with 1 mg/mL of purified recombined proteins SPLUNC1-hFc, mE3-hFc, (13) and human IgG1-Fc. 100 mL cultured supernatant or diluted purified antibody and horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG-Fc antibody were successively added.…”

Section: Characteristics Of Monoclonal Antibodiesmentioning

confidence: 99%

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SPLUNC1 Is a Significant Marker in Pleural Effusion from Lung Cancer Compared to Tuberculosis

Xue

Yan

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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SPLUNC1 (Short palate, lung and nasal epithelium clone1) protein is an abundant secretory product of epithelia present throughout the conducting airways. Although its function is still not fully known, most studies have focused on its defensive effect in the infection of human airways and its potential to serve as a molecular marker for lung cancer. In this study, we further evaluated the SPLUNC1 expression in patients with lung disease to explore its role in cancer or tuberculosis at the protein level. We generated a panel of antibodies by using protein from a eukaryotic expression system as the immunogen to mice. It was the panel of SPLUNC1 monoclonal antibodies that allowed us to comparatively determine SPLUNC1 protein in lung cancer and tuberculosis infection by detecting sera and pleural effusion other than airway surface. The results showed that the SPLUNC1 level was not significantly changed either from sera of lung cancer or control. There was a significant increase in pleural effusion from lung cancer when compared to tuberculosis. These results indicate that SPLUNC1 may be a useful marker for tracing lung cancer cells, based on its epithelial origin property in pleural effusion.

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Human and Mouse CD137 Have Predominantly Different Binding CRDs to Their Respective Ligands

Cited by 13 publications

References 42 publications

Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice

Inhibition of 4‐1BBL‐regulated TLR response in macrophages ameliorates endotoxin‐induced sepsis in mice

Crystal structure of the m4-1BB/4-1BBL complex reveals an unusual dimeric ligand that undergoes structural changes upon 4-1BB receptor binding

SPLUNC1 Is a Significant Marker in Pleural Effusion from Lung Cancer Compared to Tuberculosis

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