title: Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation.
abstract: 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-kappaB 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-kappaB. 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 (162)PVPAT(166) in BAFF-R is accommodated in the same binding crevice on TRAF3 that binds two related TNFRs, CD40 and LTbetaR, 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 Gln(379) 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 Tyr(377) 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.
authors.affiliation: Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
authors.forename: Chao-Zhou
authors.initials: CZ
authors.lastname: Ni
authors.forename: Gagik
authors.initials: G
authors.lastname: Oganesyan
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Zhu
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Arnold C
authors.initials: AC
authors.lastname: Satterthwait
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Ely
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D053265:B-Cell Activation Factor Receptor; D008565:Membrane Proteins; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3; C435926:TNFRSF13C protein, human