5cem | pdb_00005cem
Pseudokinase and C-terminal extension of Human Tribbles Homolog 1
Structural highlights
FunctionTRIB1_HUMAN Interacts with MAPK kinases and regulates activation of MAP kinases. May not display kinase activity.[1] [2] Publication Abstract from PubMedCCAAT-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. Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase.,Murphy JM, Nakatani Y, Jamieson SA, Dai W, Lucet IS, Mace PD Structure. 2015 Nov 3;23(11):2111-21. doi: 10.1016/j.str.2015.08.017. Epub 2015, Oct 9. PMID:26455797[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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