HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ni, C.-Z. Articles by Ely, K. R. Search for Related Content PubMed PubMed Citation Articles by Ni, C.-Z. Articles by Ely, K. R. Pubmed/NCBI databases Domain Gene GEO Profiles HomoloGene Protein Structure UniGene Substance via MeSH

Key Molecular Contacts Promote Recognition of the BAFF Receptor by TNF Receptor-Associated Factor 3: Implications for Intracellular Signaling Regulation¹

Chao-Zhou Ni^*, Gagik Oganesyan, Kate Welsh^*, Xiuwen Zhu^*, John C. Reed^*, Arnold C. Satterthwait^*, Genhong Cheng^, and Kathryn R. Ely^2,*

^* Cancer Research Center, The Burnham Institute, La Jolla, CA 92037; and Microbiology, Immunology and Molecular Genetics and Johnsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095

B cell-activating factor belonging to the TNF family receptor (BAFF-R), a member of the TNFR superfamily, plays a role in autoimmunity after ligation with BAFF ligand (also called TALL-1, BLyS, THANK, or zTNF4). BAFF/BAFF-R interactions are critical for B cell regulation, and signaling from this ligand-receptor complex results in NF-B activation. Most TNFRs transmit signals intracellularly by recruitment of adaptor proteins called TNFR-associated factors (TRAFs). However, BAFF-R binds only one TRAF adaptor, TRAF3, and this interaction negatively regulates activation of NF-B. In this study, we report the crystal structure of a 24-residue fragment of the cytoplasmic portion of BAFF-R bound in complex with TRAF3. The recognition motif ¹⁶²PVPAT¹⁶⁶ in BAFF-R is accommodated in the same binding crevice on TRAF3 that binds two related TNFRs, CD40 and LTR, but is presented in a completely different structural framework. This region of BAFF-R assumes an open conformation with two extended strands opposed at right angles that each make contacts with TRAF3. The recognition motif is located in the N-terminal arm and intermolecular contacts mediate TRAF recognition. In the C-terminal arm, key stabilizing contacts are made, including critical hydrogen bonds with Gln³⁷⁹ in TRAF3 that define the molecular basis for selective binding of BAFF-R solely to this member of the TRAF family. A dynamic conformational adjustment of Tyr³⁷⁷ in TRAF3 occurs forming a new intermolecular contact with BAFF-R that stabilizes the complex. The structure of the complex provides a molecular explanation for binding affinities and selective protein interactions in TNFR-TRAF interactions.

This article has been cited by other articles:

				E. Braggio, J. J. Keats, X. Leleu, S. Van Wier, V. H. Jimenez-Zepeda, R. Valdez, R. F.J. Schop, T. Price-Troska, K. Henderson, A. Sacco, et al. Identification of Copy Number Abnormalities and Inactivating Mutations in Two Negative Regulators of Nuclear Factor-{kappa}B Signaling Pathways in Waldenstrom's Macroglobulinemia Cancer Res., April 15, 2009; 69(8): 3579 - 3588. [Abstract] [Full Text] [PDF]

				J. P. Miller, J. E. Stadanlick, and M. P. Cancro Space, Selection, and Surveillance: Setting Boundaries with BLyS. J. Immunol., June 1, 2006; 176(11): 6405 - 6410. [Abstract] [Full Text] [PDF]

				S. Wu, P. Xie, K. Welsh, C. Li, C.-Z. Ni, X. Zhu, J. C. Reed, A. C. Satterthwait, G. A. Bishop, and K. R. Ely LMP1 Protein from the Epstein-Barr Virus Is a Structural CD40 Decoy in B Lymphocytes for Binding to TRAF3 J. Biol. Chem., September 30, 2005; 280(39): 33620 - 33626. [Abstract] [Full Text] [PDF]