PDBsum entry 1p0t

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(+ 54 more) 25 a.a.

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Title Crystal structure of the baff-Baff-R complex and its implications for receptor activation.
Authors H.M.Kim, K.S.Yu, M.E.Lee, D.R.Shin, Y.S.Kim, S.G.Paik, O.J.Yoo, H.Lee, J.O.Lee.
Ref. Nat Struct Biol, 2003, 10, 342-348. [DOI no: 10.1038/nsb925]
PubMed id 12715002
B-cell activating factor (BAFF) is a key regulator of B-lymphocyte development. Its biological role is mediated by the specific receptors BCMA, TACI and BAFF-R. We have determined the crystal structure of the extracellular domain of BAFF-R bound to BAFF at a resolution of 3.3 A. The cysteine-rich domain (CRD) of the BAFF-R extracellular domain adopts a beta-hairpin structure and binds to the virus-like BAFF cage in a 1:1 molar ratio. The conserved DxL motif of BAFF-R is located on the tip of the beta-turn and is indispensable in the binding of BAFF. The crystal structure shows that a unique dimeric contact occurs between the BAFF-R monomers in the virus-like cage complex. The extracellular domain of TACI contains two CRDs, both of which contain the DxL motif. Modeling of TACI-BAFF complex suggests that both CDRs simultaneously interact with the BAFF dimer in the virus-like cage.
Figure 1.
Figure 1. Structure of the BAFF-R extracellular domains bound to the virus-like BAFF cage. a, Stereo view of a [A]-weighted, simulated annealing, F[o] - F[c] omit electron density map (1.5 ). The residues located within 5 from Leu28 of BAFF-R were omitted for the map calculation. b,c, Overall structure of the BAFF -BAFF-R complex looking down the five-fold axis (b) and looking down the three-fold axis (c). The molecular surface of the BAFF cage is drawn in gray, and the dimeric pairs of BAFF-R are drawn in blue and red. d, A close-up view of the BAFF and BAFF-R complex. Viewing orientation is similar to that of c. The subunits of the BAFF-R dimers are shown in blue and red and are enclosed in boxes. The BAFF dimers are colored green, yellow or gray.
Figure 5.
Figure 5. Characterization of the BAFF and TACI interaction. a, Binding of TACI CRD1 (residues 14 -69) and CRD2 (residues 67 -111) to BAFF. The conserved Asp and Leu residues of the DxL motifs are mutated to alanines in the mutants (M). The TACI FL is the extracellular domain (residues 1 -156) of the full-length TACI. After the binding assay, the resulting duplicate SDS-PAGE gels were visualized either by Coomassie staining or by immunoblot analysis using a polyclonal antibody specific to BAFF (Upstate Biotech) (see Methods). b, Interaction of the TACI CRDs with BAFF. C1M contains mutations of Asp41 and Leu43 of the first DxL motif to alanines. C2M contains mutations of Asp80 and Leu82 of the second DxL motif to alanines. C1,2M contains simultaneous double alanine mutations of both DxL motifs of TACI FL. The resulting duplicate SDS-PAGE gels were visualized as in a. c, CRD1 and CRD2 share the same binding site as BAFF. BAFF DE has a deletion of the DE loop. The R265A BAFF DE mutant has a mutation of Arg265 to alanine and a deletion of the DE loop. C1M, C2M and C1,2M are TACI mutants, as described in b. The resulting duplicate SDS-PAGE gels were visualized as in a. The flexible His[6] tag of the BAFF DE mutant was partially digested during purification and runs as a diffuse band in the SDS-PAGE gel. d, Model of the TACI extracellular domain bound to BAFF. The TACI extracellular domain (residues 32 -104) is shown in a broken black line. Negatively and positively charged surfaces of BAFF are colored red and blue, respectively. The N and C termini of the TACI extracellular domain are indicated. Viewing orientation is similar to that of Fig. 3b. A1 and C2 modules of CRDs are indicated. The structures of the A1 modules were built with that of BAFF-R CRD as a template. The structures of the C2 modules and the angles between the A1 and C2 modules were adopted from the structure of TNFR1 CRD4 for model building. The molecular modeling was carried out using WHATIF^43.
The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 342-348) copyright 2003.
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