Structures of APRIL-receptor complexes - Like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding

被引:132
作者
Hymowitz, SG
Patel, DR
Wallweber, HJA
Runyon, S
Yan, MH
Yin, JP
Shriver, SK
Gordon, NC
Pan, BL
Skelton, NJ
Kelley, RF
Starovasnik, MA
机构
[1] Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Med Chem, San Francisco, CA 94080 USA
[4] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA
关键词
D O I
10.1074/jbc.M411714200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 cocrystal 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.
引用
收藏
页码:7218 / 7227
页数:10
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