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    A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors

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    Author
    Vigolo, M; Chambers, MG; Willen, L; Chevalley, D; Maskos, K; Lammens, A; Tardivel, A; Das, D; Kowalczyk-Quintas, C; Schuepbach-Mallepell, S; ...
    Date
    2018-03-23
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Mackay, Fabienne
    Affiliation
    Microbiology and Immunology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Vigolo, M., Chambers, M. G., Willen, L., Chevalley, D., Maskos, K., Lammens, A., Tardivel, A., Das, D., Kowalczyk-Quintas, C., Schuepbach-Mallepell, S., Smulski, C. R., Eslami, M., Rolink, A., Hummler, E., Samy, E., Nanfack, Y. F., Mackay, F., Liao, M., Hess, H. ,... Schneider, P. (2018). A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-03323-8.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/254775
    DOI
    10.1038/s41467-018-03323-8
    Abstract
    The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.

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