Ligand–receptor binding revealed by the TNF family member TALL-1

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 A, 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.

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

“…29,33 It is not known whether the activity of BAFF is conditioned by its level of oligomerization, such as those found in BAFF 3-mer and BAFF 60-mer. 13,34 To monitor the activity of BAFF 3-mer and oligomers, a surrogate cell death assay was developed, in which the oligomerization-dependent apoptotic Fas pathway can be initiated by BAFF. For this purpose, a fusion protein consisting of the extracellular domain of BCMA fused to the transmembrane and intracellular domains of Fas was expressed in Jurkat T cells.…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…For example, a TNF family member, sTALL, was found to be an ensemble of 60 monomer units interacting non-covalently to generate a symmetric "virus-like" complex. [94,111,112] It is hypothesized that geometric complexity of sTALL is required to organize multiple copies of its cell surface receptor into an active signaling complex. Other natural ligands, such as lipopolysaccharides, mucins, and glycosaminoglycans, present a heterogeneous display of potential receptor binding sites, even within the same molecule.…”

The role of APRIL and BAFF in lymphocyte activation

“…The hairpin is alone sufficient for BAFF binding [1 ,7,9,10], but binding to APRIL requires a specific hydrophobic residue in the hairpin that is found in TACI and BCMA but not in BAFF-R [1 ,2]. In addition, the variable motif of BAFF-R is detrimental for APRIL binding, which explains the exquisite specificity of BAFF-R for BAFF but not APRIL [7], whereas the corresponding motifs of TACI and BCMA promote different interactions with ligands and are therefore likely to dictate the differential affinity for BAFF [1 ,2]. BAFF and APRIL have additional structural features of uncertain physiological relevance.…”

“…BAFF can also heterotrimerize with APRIL in undefined stoichiometry [14], although this process appears to be far less efficient than the heterotrimerization of lymphotoxin a 1 b 2 , a well-characterized heterotrimer of the TNF family. Finally, recombinant soluble BAFF trimers have a pH-dependent propensity to form spherical structures composed of 20 trimers, whose specific signaling properties largely remain to be explored [7,9,15].…”