1. Integrated Department of Immunology, National Jewish Medical and Research Center, Howard Hughes Medical Institute, and Department of Pharmacology, Biomolecular Structure Program, School of Medicine, University of Colorado Health Science Center, 1400 Jackson Street, Denver, Colorado 80206, USA
2. Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, China
3. Structural Biology Section, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA
4. These authors contributed equally to this work

Correspondence to: Gongyi Zhang^1,4 Correspondence and requests for materials should be addressed to G.Z. (Email: zhangg@njc.org). The atomic coordinates and reflections have been deposited in the Protein Data Bank under accession codes 1OQD and 1OQE.

Abstract

The tumour necrosis factor (TNF) ligand TALL-1 and its cognate receptors, BCMA, TACI and BAFF-R, were recently identified as members of the TNF superfamily, which are essential factors contributing to B-cell maturation. The functional, soluble fragment of TALL-1 (sTALL-1) forms a virus-like assembly for its proper function. Here we determine the crystal structures of sTALL-1 complexed with the extracellular domains of BCMA and BAFF-R at 2.6 and 2.5 Å, respectively. The single cysteine-rich domain of BCMA and BAFF-R both have saddle-like architectures, which sit on the horseback-like surface formed by four coil regions on each individual sTALL-1 monomer. Three novel structural modules, D2, X2 and N, were revealed from the current structures. Sequence alignments, structural modelling and mutagenesis revealed that one disulphide bridge in BAFF-R is critical for determining the binding specificity of the extracellular domain eBAFF-R to TALL-1 instead of APRIL, a closely related ligand of TALL-1, which was confirmed by binding experiments in vitro.