No abstract

Of all the antibody classes, IgE displays a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcεRI. The structural basis for these key determinants of IgE's ability to mediate allergic hypersensitivity is now revealed by the 3.4Å resolution crystal structure of human IgE-Fc (consisting of the Cε2, Cε3 and Cε4 domains) bound to the extracellular domains of the FcεRI α-chain. Comparison with free IgE-Fc (reported here at 1.9Å) shows that the antibody, which has a compact, bent structure prior to receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the non-contacting Cε2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to IgE's unique binding properties.The global incidence of allergic disease has increased markedly in recent years and continues to rise. Asthma currently affects 22.2 million people in North America and 5.4 million in the UK where the rate of incidence, especially in children, is among the highest in the world 1 . Anaphylactic reactions to foods such as nuts, virtually unknown thirty years ago, are now relatively common. The reason for this increase is debated, but these and other allergic conditions (rhinitis, eczema etc.) are all mediated by IgE, and the viability of AUTHOR CONTRIBUTIONS MDH and AMD carried out the crystallographic analysis of the complex, and BD the crystallographic analysis of IgE-Fc; MDH, JEN, JH, AJB and RJO produced the proteins; SCB and JMM carried out the thermodynamic analysis; EG contributed to the analysis of the conformational changes; HJG, AJB and BJS planned and directed the project; MDH, AMD, JMM and BJS wrote the paper.Accession codes. Atomic coordinates and structure factors have been deposited in the Protein Data Bank with entry codes 2WQR for IgE-Fc and 2Y7Q for the complex. [6][7][8][9] . Particular interest has centered on the role of the Cε2 domains, which were shown to contribute to the slow dissociation rate 10 , by comparing the binding kinetics of the complete IgE-Fc (dimer Cε2-Cε3-Cε4 domains) with a sub-fragment lacking the Cε2 domains, here referred to as Fcε3-4. The Cε2 domains have no counterpart in IgG, all four subclasses of which have in their place hinge regions of various lengths and degrees of flexibility. Europe PMC Funders GroupEarly fluorescence resonance energy transfer (FRET) studies of labelled chimeric IgE indicated a more compact and bent structure than the extended, flexible Y-shaped IgG 11 , and later solution scattering studies of IgE-Fc were consistent with such a structure 12 . The crystal structure of IgE-Fc revealed for the first time the extent and nature of this bend 13 , made possible by the presence of the Cε2 domains. Surprisingly the molecule was found to be so acutely and asymmetrically bent, with the Cε2 domain pair folded back across the Cε3 domains, that one Cε2 domain even contacted the Cε4 domai...

In the last two decades, a variety of fungal antioxidants have attracted considerable interest, largely arising from their hypothetical role as virulence determinants. Melanin is a potent free radical scavenger and in Cryptococcus neoformans, there is now good evidence that the production of melanin is a significant virulence determinant. There is also recent evidence linking melanin biosynthesis to the virulence of Aspergillus fumigatus conidia. Superoxide dismutases are important housekeeping antioxidants and have an additional hypothetical role in virulence; however, although these enzymes have been biochemically characterized from Aspergillus and Cryptococcus, there is as yet no firm evidence that these enzymes are involved in pathogenicity. Catalase production may play some role in the virulence of Candida albicans but this enzyme has not been shown, as yet, to influence the virulence of A. fumigatus. There are some data supporting an antioxidant function for the acyclic hexitol mannitol in C. neoformans, but further investigations are required in this area. Research into the putative antioxidant activities of a range of other fungal enzymes, such as acid phosphatases, remains limited at this time.