Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain.
Lauenstein, Johannes U
Moncrieffe, Martin C
Fisher, David I
Journal of immunology (Baltimore, Md. : 1950)
American Association of Immunologists
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Lauenstein, J. U., Scherm, M. J., Udgata, A., Moncrieffe, M. C., Fisher, D. I., & Gay, N. (2020). Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain.. Journal of immunology (Baltimore, Md. : 1950), 204 (8), 2269-2276. https://doi.org/10.4049/jimmunol.1901210
The B-cell adaptor protein (BCAP) is a multi-modular regulator of inflammatory signalling in diverse immune system cells. BCAP couples Toll-like receptor signalling to phosphoinositide metabolism and inhibits MyD88 directed signal transduction. BCAP is recruited to the TLR signalosome forming multi-typic interactions with the MAL and MyD88 signalling adaptors. Here we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signalling. This regulation is mediated by a transcription factor immunoglobulin (TIG/IPT) domain, a fold found in the NFB 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 -sheets of the immunoglobulin 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.
Cells, Cultured, Humans, Adaptor Proteins, Signal Transducing, Immunoglobulins, Signal Transduction, Toll-Like Receptors, Myeloid Differentiation Factor 88, Protein Multimerization, HEK293 Cells, THP-1 Cells
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External DOI: https://doi.org/10.4049/jimmunol.1901210
This record's URL: https://www.repository.cam.ac.uk/handle/1810/303284
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