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- Title
Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1.
- Authors
Jamieson, Sam A.; Ruan, Zheng; Burgess, Abigail E.; Curry, Jack R.; McMillan, Hamish D.; Brewster, Jodi L.; Dunbier, Anita K.; Axtman, Alison D.; Kannan, Natarajan; Mace, Peter D.
- 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.
- Subjects
CARRIER proteins; FAT cells; MYELOID leukemia; TRANSCRIPTION factors; MOLECULAR dynamics
- Publication
Science Signaling, 2018, Vol 11, Issue 549, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aau0597