Research Publications


Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase

Murphy, JM; Nakatani, Y; Jamieson, SA; Dai, W; Lucet, IS; Mace, PD
Journal Article
CCAAT-enhancer binding proteins (C/EBPs) are transcription factors that play a central role in the differentiation of myeloid cells and adipocytes. Tribbles pseudokinases govern levels of C/EBPs by recruiting them to the COP1 ubiquitin ligase for ubiquitination. Here, we present the first crystal structure of a Tribbles protein, which reveals a catalytically inactive TRIB1 pseudokinase domain with a unique adaptation in the alphaC helix. A second crystal structure and biophysical studies of TRIB1 with its C-terminal extension, which includes the COP1-binding motif, show that the C-terminal extension is sequestered at a site formed by the modified TRIB1 alphaC helix. In addition, we have identified and characterized the TRIB1 substrate-recognition sequence within C/EBPalpha, which is evolutionarily conserved in C/EBP transcription factors. Binding studies indicate that C/EBPalpha recruitment is weaker in the presence of the C-terminal COP1-binding motif, but the magnitude of this effect suggests that the two bind distinct rather directly overlapping binding sites.
Cell Press
Chemical Biology; Cell Signalling and Cell Death
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