Expression and Purification of a Natural N-Terminal Pre-ligand Assembly Domain of Tumor Necrosis Factor Receptor 1 (TNFR1 PLAD) and Preliminary Activity Determination

Cao, Jun; Fang, Meng; Gao, Xiangdong; Dong, Hongxia; Yao, Wenbing

doi:10.1007/s10930-011-9330-4

Cited by 19 publications

(12 citation statements)

References 28 publications

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“…It is noteworthy that the homotypic PLAD affinity is rather low, almost in the mM range (Cao et al, 2011) suggesting that other domains in CD95 could exert a complementary role for the receptor homotrimerization, in agreement with the proposed trimeric model. FIGURE 2 | CD95 sequence and structure.…”

Section: Extracellular Regionsupporting

confidence: 82%

CD95 Structure, Aggregation and Cell Signaling

Levoin

Jean

Legembre

2020

Front. Cell Dev. Biol.

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CD95 is a pre-ligand-associated transmembrane (TM) receptor. The interaction with its ligand CD95L brings to a next level its aggregation and triggers different signaling pathways, leading to cell motility, differentiation or cell death. This diversity of biological responses associated with a unique receptor devoid of enzymatic property raises the question of whether different ligands exist, or whether the fine-tuned control of CD95 aggregation and conformation, its distribution within certain plasma membrane subdomains or the pattern of post-translational modifications account for this such broadrange of cell signaling. Herein, we review how the different domains of CD95 and their post-translational modifications or the different forms of CD95L can participate in the receptor aggregation and induction of cell signaling. Understanding how CD95 response goes from cell death to cell proliferation, differentiation and motility is a prerequisite to reveal novel therapeutic options to treat chronic inflammatory disorders and cancers.

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Section: Extracellular Regionsupporting

confidence: 82%

CD95 Structure, Aggregation and Cell Signaling

Levoin

Jean

Legembre

2020

Front. Cell Dev. Biol.

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“…It is noteworthy that the affinity of the PLAD–PLAD interaction is rather low and almost in the mM range. 14 This corresponds to the observation that soluble TNFRSF receptor ectodomains are typically very poor TNFSF ligand agonists unless they are fused with multimerizing scaffolds. In view of the weak PLAD-PLAD affinity an unclear aspect of the PLAD-based TNFRSF receptor activation model concerns the equilibrium between monomeric and PLAD-assembled TNFRSF receptors.…”

Section: General Principles Of Tnfrsf Receptor Activation By Ligands mentioning

confidence: 76%

Principles of antibody-mediated TNF receptor activation

2015

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From the beginning of research on receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF), agonistic antibodies have been used to stimulate TNFRSF receptors in vitro and in vivo. Indeed, CD95, one of the first cloned TNFRSF receptors, was solely identified as the target of cell death-inducing antibodies. Early on, it became evident from in vitro studies that valency and Fcγ receptor (FcγR) binding of antibodies targeting TNFRSF receptors can be of crucial relevance for agonistic activity. TNFRSF receptor-specific antibodies of the IgM subclass and secondary cross-linked or aggregation prone dimeric antibodies typically display superior agonistic activity compared with dimeric antibodies. Likewise, anchoring of antibodies to cell surface-expressed FcγRs potentiate their ability to trigger TNFRSF receptor signaling. However, only recently has the relevance of oligomerization and FcγR binding for the in vivo activity of antibody-induced TNFRSF receptor activation been straightforwardly demonstrated in vivo. This review discusses the crucial role of oligomerization and/or FcγR binding for antibody-mediated TNFRSF receptor stimulation in light of current models of TNFRSF receptor activation and especially the overwhelming relevance of these issues for the rational development of therapeutic TNFRSF receptor-targeting antibodies.

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“…Such PLAD is supported by experiments involving biochemical crosslinking of cell surface receptors, FRET, and more recently by super-resolution microscopy 29 . However, evidence for PLAD-PLAD interaction between recombinantly expressed CRD1 domains remains unclear, likely due to its low-affinity interaction rendering routine biophysical measurements difficult 30 . The idea that each PLAD serves as a receptor-specific regulatory element for self-assembly offers a mechanism for the differential sensitivity of TNFRs to various forms of agonist.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a dysfunctional PLAD restricted TNFR1 to monomers even in the presence of TNF-α 29 . Further biophysical characterisations of recombinant PLADs of TNFR1 and TNFR2 detected some specific, albeit weak, PLAD-PLAD interactions 30 .…”

mentioning

confidence: 91%

TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity

James

Felce

et al. 2021

Commun Biol

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Monoclonal antibodies (mAb) and natural ligands targeting costimulatory tumor necrosis factor receptors (TNFR) exhibit a wide range of agonistic activities and antitumor responses. The mechanisms underlying these differential agonistic activities remain poorly understood. Here, we employ a panel of experimental and clinically-relevant molecules targeting human CD40, 4-1BB and OX40 to examine this issue. Confocal and STORM microscopy reveal that strongly agonistic reagents induce clusters characterized by small area and high receptor density. Using antibody pairs differing only in isotype we show that hIgG2 confers significantly more receptor clustering than hIgG1 across all three receptors, explaining its greater agonistic activity, with receptor clustering shielding the receptor-agonist complex from further molecular access. Nevertheless, discrete receptor clustering patterns are observed with different hIgG2 mAb, with a unique rod-shaped assembly observed with the most agonistic mAb. These findings dispel the notion that larger receptor clusters elicit greater agonism, and instead point to receptor density and subsequent super-structure as key determinants.

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Expression and Purification of a Natural N-Terminal Pre-ligand Assembly Domain of Tumor Necrosis Factor Receptor 1 (TNFR1 PLAD) and Preliminary Activity Determination

Cited by 19 publications

References 28 publications

CD95 Structure, Aggregation and Cell Signaling

CD95 Structure, Aggregation and Cell Signaling

Principles of antibody-mediated TNF receptor activation

TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity

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