Download MendeleyA loop region of BAFF controls B cell survival and regulates recognition by different inhibitors.
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., Fomekong Nanfack, Y., Mackay, F., Liao, M., Hess, H., Jiang, X., Schneider, P.(2018) Nat Commun 9: 1199-1199
- PubMed: 29572442
- DOI: https://doi.org/10.1038/s41467-018-03323-8
- Primary Citation of Related Structures:
6FXN - PubMed 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.
Organizational Affiliation:
Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
