Substrate binding allosterically relieves autoinhibition of the TRIB1 pseudokinase

摘要: The Tribbles family of pseudokinases recruit substrates to the COP1 ubiquitin ligase for ubiquitination. CCAAT-enhancer binding protein (C/EBP) transcription factors are crucial in adipocyte and myeloid development. Here we show that TRIB1 pseudokinase can various C/EBP members, with C/EBPβ attenuated by phosphorylation. To explain mechanism substrate recruitment, solved crystal structure complex C/EBPα. undergoes a significant conformational change relative its substrate-free structure, bind C/EBPα pseudo-substrate-like manner. Crucially, triggers allosteric changes link recruitment binding, which is consistent molecular dynamics biochemical studies. These findings offer view regulation striking parallels bona fide kinase regulation, via activation loop αC-helix, raise possibility small molecules targeting either loop-in, or loop-out, conformations pseudokinases.