Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding.
TACI is a member of the tumor necrosis factor receptor superfamily and serves as a key regulator of B cell function. TACI binds two ligands, APRIL and BAFF, with high affinity and contains two cysteine-rich domains (CRDs) in its extracellular region; in contrast, BCMA and BR3, the other known high affinity receptors for APRIL and BAFF, respectively, contain only a single or partial CRD. However, another form of TACI exists wherein the N-terminal CRD is removed by alternative splicing. We find that this shorter form is capable of ligand-induced cell signaling and that the second CRD alone (TACI_d2) contains full affinity for both ligands. Furthermore, we report the solution structure and alanine-scanning mutagenesis of TACI_d2 along with co-crystal structures of APRIL.TACI_d2 and APRIL.BCMA complexes that together reveal the mechanism by which TACI engages high affinity ligand binding through a single CRD, and we highlight sources of ligand-receptor specificity within the APRIL/BAFF system.
Hymowitz
Sarah G
SG
Department of Protein Engineering, Molecular Oncology, Medicinal Chemistry, and Immunology, Genentech, Inc., South San Francisco, California 94080, USA.
Patel
Darshana R
DR
Wallweber
Heidi J A
HJ
Runyon
Steven
S
Yan
Minhong
M
Yin
Jianping
J
Shriver
Stephanie K
SK
Gordon
Nathaniel C
NC
Pan
Borlan
B
Skelton
Nicholas J
NJ
Kelley
Robert F
RF
Starovasnik
Melissa A
MA
D017398:Alternative Splicing; D000818:Animals; D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D003460:Crystallization; D018360:Crystallography, X-Ray; D003545:Cysteine; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction; D012996:Solutions; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry*
D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D008024:Ligands; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D012996:Solutions; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; D003545:Cysteine