BAFF/BLyS Receptor 3 Comprises a Minimal TNF Receptor-like Module That Encodes a Highly Focused Ligand-Binding Site
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- 作者：Nathaniel C. Gordon ; Borlan Pan ; Sarah G. Hymowitz ; JianPing Yin ; Robert F. Kelley ; Andrea G. Cochran ; Minhong Yan ; Vishva M. Dixit ; Wayne J. Fairbrother ; and Melissa A. Starovasnik
- 刊名：Biochemistry
- 出版年：2003
- 出版时间：May 27, 2003
- 年：2003
- 卷：42
- 期：20
- 页码：5977 - 5983
- 全文大小：308K
- 年卷期：v.42,no.20(May 27, 2003)
- ISSN：1520-4995
文摘
BAFF/BLyS, a member of the tumor necrosis family (TNF) superfamily of ligands, is a crucialsurvival factor for B cells. BAFF binds three receptors, TACI, BCMA, and BR3, with signaling throughBR3 being essential for promoting B cell function. Typical TNF receptor (TNFR) family members bindtheir cognate ligands through interactions with two cysteine-rich domains (CRDs). However, theextracellular domain (ECD) of BR3 consists of only a partial CRD, with cysteine spacing distinct fromother modules described previously. Herein, we report the solution structure of the BR3 ECD. A coreregion of only 19 residues adopts a stable structure in solution. The BR3 fold is analogous to the first halfof a canonical TNFR CRD but is stabilized by an additional noncanonical disulfide bond. BAFF-bindingdeterminants were identified by shotgun alanine-scanning mutagenesis of the BR3 ECD expressed onphage. Several of the key BAFF-binding residues are presented from a 
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-turn that we have shown previouslyto be sufficient for ligand binding when transferred to a structured ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-hairpin scaffold [Kayagaki, N., Yan,M., Seshasayee, D., Wang, H., Lee, W., French, D. M., Grewal, I. S., Cochran, A. G., Gordon, N. C.,Yin, J., Starovasnik, M. A, and Dixit, V. M. (2002) Immunity 10, 515-524]. Outside of the turn,mutagenesis identifies additional hydrophobic contacts that enhance the BAFF-BR3 interaction. Thecrystal structure of the minimal hairpin peptide, bhpBR3, in complex with BAFF reveals intimate packingof the six-residue BR3 turn into a cavity on the ligand surface. Thus, BR3 binds BAFF through a highlyfocused interaction site, unprecedented in the TNFR family.