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Nat Commun. 2018 Mar 23;9(1):1199. doi: 10.1038/s41467-018-03323-8.

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

Author information

1
Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland.
2
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
3
Proteros Biostructures GmbH, 82152, Planegg, Germany.
4
Department of Biomedicine, University of Basel, 4058, Basel, Switzerland.
5
Department of Pharmacology and Toxicology, University of Lausanne, 1011, Lausanne, Switzerland.
6
EMD Serono Research & Development Institute, Billerica, MA, 01821, USA.
7
Department of Immunology, Monash University, Melbourne, VIC, 3004, Australia.
8
Merck KGaA, 64293, Darmstadt, Germany.
9
Department of Biochemistry, University of Lausanne, 1066, Epalinges, Switzerland. pascal.schneider@unil.ch.

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.

PMID:
29572442
PMCID:
PMC5865128
DOI:
10.1038/s41467-018-03323-8
[Indexed for MEDLINE]
Free PMC Article

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