Human immunoglobulin E flexes between acutely bent and extended conformations

Drinkwater, N.; Cossins, Benjamin P.; Keeble, Anthony H.; Wright, Michael; Cain, Katharine; Hailu, Hanna; Oxbrow, Amanda K. F.; Delgado, Jean; Shuttleworth, Lindsay K.; Kao, Michael W.; McDonnell, James M.; Beavil, Andrew J.; Henry, Alistair J.; Sutton, Brian J.

doi:10.1038/nsmb.2795

Cited by 54 publications

(107 citation statements)

References 69 publications

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“…Structural studies of secreted IgE indicated that an asymmetric bend can occur in IgE at the CH2-CH3 linker region, causing one of the two CH2 domains to fold back onto the CH3 and CH4 domains, making particularly extensive contacts with the CH3 domain (Wan et al, 2002). Recent evidence suggests that this bent shape can also be extended, which can subsequently allow CH2 to flip from one side of CH3-CH4 to the other (Drinkwater et al, 2014). It seems plausible that for the membrane IgE BCR, the ability to adopt an asymmetric bend conformation mimics antigen binding.…”

Section: Discussionmentioning

confidence: 99%

Regulation of B cell fate by chronic activity of the IgE B cell receptor

Yang

Robinson

Chen

et al. 2016

eLife

131

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IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.DOI: http://dx.doi.org/10.7554/eLife.21238.001

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Section: Discussionmentioning

confidence: 99%

Regulation of B cell fate by chronic activity of the IgE B cell receptor

Yang

Robinson

Chen

et al. 2016

eLife

131

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“…IgY is evolutionarily most closely related to IgG and IgE (2). Similar to IgY, IgE does not have a hinge, and recent studies indicate that the Fc portion of this molecule folds back upon itself (31), which may explain the unusual appearance of the Fc in 7S IgY. Other Igs also have flexible Fc.…”

Section: Discussionmentioning

confidence: 98%

Green Turtles (Chelonia mydas) Have Novel Asymmetrical Antibodies

Work

Dagenais

Breeden

et al. 2015

The Journal of Immunology

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Igs in vertebrates comprise equally sized H and L chains, with exceptions such as H chain–only Abs in camels or natural Ag receptors in sharks. In Reptilia, Igs are known as IgYs. Using immunoassays with isotype-specific mAbs, in this study we show that green turtles (Chelonia mydas) have a 5.7S 120-kDa IgY comprising two equally sized H/L chains with truncated Fc and a 7S 200-kDa IgY comprised of two differently sized H chains bound to L chains and apparently often noncovalently associated with an antigenically related 90-kDa moiety. Both the 200- and 90-kDa 7S molecules are made in response to specific Ag, although the 90-kDa molecule appears more prominent after chronic Ag stimulation. Despite no molecular evidence of a hinge, electron microscopy reveals marked flexibility of Fab arms of 7S and 5.7S IgY. Both IgY can be captured with protein G or melon gel, but less so with protein A. Thus, turtle IgY share some characteristics with mammalian IgG. However, the asymmetrical structure of some turtle Ig and the discovery of an Ig class indicative of chronic antigenic stimulation represent striking advances in our understanding of immunology.

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“…Interestingly the complementarity-determining region, CDR3 H3 loop, of the Fab fragment penetrated deep into the GPCR, mimicking the CDR3 of the VHH in the Rasmussen paper [25], and showing that extended CDR loops are not the sole preserve of nanobodies. While GPCRs have been the focus of much of the pioneering work with antibody fragment-definition of conformations, a new perspective on IgE function in allergen recognition has been achieved through study of a diversity of conformational states [29]. A function-modifying antibody Fab fragment was shown to hold the Cε2 and Cε3 domains in a linear structure which precluded receptor binding, validating molecular dynamics predictions of IgE Fc conformational sampling.…”

Section: Definition Of Functionally Relevant Conformations Of Proteinsmentioning

confidence: 98%

Antibody Fragments Defining Biologically Relevant Conformations of Target Proteins

Lawson¹

2014

Antibodies

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Antibody fragments have long been used as chaperones in crystallography, but have more recently been applied to the definition of biologically relevant conformations among the dynamic ensemble of target protein conformational sampling. This review charts the progress being made in understanding function in the context of structure using this approach, and highlights new opportunities for drug discovery.

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Human immunoglobulin E flexes between acutely bent and extended conformations

Cited by 54 publications

References 69 publications

Regulation of B cell fate by chronic activity of the IgE B cell receptor

Regulation of B cell fate by chronic activity of the IgE B cell receptor

Green Turtles (Chelonia mydas) Have Novel Asymmetrical Antibodies

Antibody Fragments Defining Biologically Relevant Conformations of Target Proteins

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