Abstract
The B cell adaptor protein (BCAP) is a multimodular regulator of inflammatory signaling in diverse immune system cells. BCAP couples TLR signaling to phosphoinositide metabolism and inhibits MyD88-directed signal transduction. BCAP is recruited to the TLR signalosome forming multitypic interactions with the MAL and MyD88 signaling adaptors. In this study, we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. This regulation is mediated by a transcription factor Ig (TIG/IPT) domain, a fold found in the NF-κB family of transcription factors. We have solved the crystal structure of the BCAP TIG and find that it is most similar to that of early B cell factor 1 (EBF1). In both cases, the dimer is stabilized by a helix-loop-helix motif at the C terminus and interactions between the β-sheets of the Ig domains. BCAP is exclusively localized in the cytosol and is unable to bind DNA. Thus, the TIG domain is a promiscuous dimerization module that has been appropriated for a range of regulatory functions in gene expression and signal transduction.
Highlights
The DBB domain was essential for this regulation because the B cell adaptor protein (BCAP) TIR domain alone was not able to reduce NF-kB signaling for both MAL and MyD88 (Fig. 1C, 1D)
Given that the expression levels of MAL and MyD88 were comparable (Fig. 1E) in all conditions, this suggests that the BCAP TIR domain interacts differently with the MAL and MyD88 TIR domain compared with longer constructs containing the DBB and ANK domain or full-length BCAP
This may be because, in the absence of the third a helix, dimerization is less stable, consistent with our structural findings (Fig. 2) (Fig. 3, Supplemental Fig. 1). These results show that the DBB domain is essential for negative regulation of TLR signaling by BCAP
Summary
We show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. Residues and interfaces in the TIR domains of the TLRs, MyD88, and MAL adaptor proteins that are required for signal transduction have been mapped [1,2,3,4,5]. BCAP links TLR signaling to phosphoinositide metabolism through heterotypic TIR domain interactions with MAL and MyD88 [11].
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