Crystal structure of the BAFF-BAFFR complex and its implications for receptor activation, crystal structure of drosophila angiotensin I-converting enzyme bound to captopril and lisinopril

Abstract

BAFF (B-cell activating factor, also termed BLyS, TALL-1, THANK, and zTNF4) is a key regulator of B-lymphocyte maturation. BAFF has sequence and structural homology with TNF family proteins. Its biological role is mediated by the specific receptors BCMA, TACI, and BAFF-R. BAFF-R appears to be the major BAFF receptor for B-cell development in vivo. We have determined the crystal structure of BAFF-R bound to BAFF at a resolution of 3.3Å. The extracellular domain of human BAFF-R were co-expressed with human BAFF in Hi5 insect cells (Invitrogen) using a recombinant baculovirus system. The BAFF/BAFF-R complexes are purified and crystallized. The BAFF-R extracellular domain adopts a β -hairpin structure, and binds to the virus-like BAFF cage in a 1:1 molar ratio. The conserved DxL motif of BAFF-R is located on the tip of the β -turn, and plays an indispensable role in the binding of BAFF. The crystal structure shows that a unique dimeric interaction occurs between the BAFF-R monomers in the virus-like cage complex. Binding of BAFF-R to trimeric BAFF induces multimerization of the complex in solution. Both the cysteine-rich domains (CRDs) of TACI contain the DxL motifs and may simultaneously interact with the BAFF dimer in the virus-like cage. We propose that in the complex with the BAFF cage, the TACI intracellular domains are arranged differently from those of BAFF-R or BCMA.