6dc0
From Proteopedia
Tribbles (TRIB1) pseudokinase fused to CCAAT-enhancer binding protein (C/EBPalpha) degron
Structural highlights
Function[TRIB1_HUMAN] Interacts with MAPK kinases and regulates activation of MAP kinases. May not display kinase activity.[1] [2] Publication Abstract from PubMedThe Tribbles family of pseudokinases recruits substrates to the ubiquitin ligase COP1 to facilitate ubiquitylation. CCAAT/enhancer-binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid cell development. We found that the TRIB1 pseudokinase was able to recruit various C/EBP family members and that the binding of C/EBPbeta was attenuated by phosphorylation. To explain the mechanism of C/EBP recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPalpha, which revealed that TRIB1 underwent a substantial conformational change relative to its substrate-free structure and bound C/EBPalpha in a pseudosubstrate-like manner. Crystallographic analysis and molecular dynamics and subsequent biochemical assays showed that C/EBP binding triggered allosteric changes that link substrate recruitment to COP1 binding. These findings offer a view of pseudokinase regulation with striking parallels to bona fide kinase regulation-by means of the activation loop and alphaC helix-and raise the possibility of small molecules targeting either the activation "loop-in" or "loop-out" conformations of Tribbles pseudokinases. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1.,Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, Dunbier AK, Axtman AD, Kannan N, Mace PD Sci Signal. 2018 Sep 25;11(549). pii: 11/549/eaau0597. doi:, 10.1126/scisignal.aau0597. PMID:30254053[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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