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Sci Signal. 2018 Sep 25;11(549). pii: eaau0597. doi: 10.1126/scisignal.aau0597.

Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1.

Author information

1
Biochemistry Department, School of Biomedical Sciences, University of Otago, P.O. Box 56, 710 Cumberland Street, Dunedin 9054, New Zealand.
2
Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.
3
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
4
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
6
Biochemistry Department, School of Biomedical Sciences, University of Otago, P.O. Box 56, 710 Cumberland Street, Dunedin 9054, New Zealand. peter.mace@otago.ac.nz.

Abstract

The 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/EBPβ was attenuated by phosphorylation. To explain the mechanism of C/EBP recruitment, we solved the crystal structure of TRIB1 in complex with C/EBPα, which revealed that TRIB1 underwent a substantial conformational change relative to its substrate-free structure and bound C/EBPα 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 αC helix-and raise the possibility of small molecules targeting either the activation "loop-in" or "loop-out" conformations of Tribbles pseudokinases.

PMID:
30254053
DOI:
10.1126/scisignal.aau0597

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