| Full text | |
| Author(s): |
Jamieson, Sam A.
;
Ruan, Zheng
;
Burgess, Abigail E.
;
Curry, Jack R.
;
Mcmilan, Hamish D.
;
Brewster, Jodi L.
;
Dunbier, Anita K.
;
Axtman, Alison D.
;
Kannan, Natarajan
;
Mace, Peter D.
Total Authors: 10
|
| Document type: | Journal article |
| Source: | SCIENCE SIGNALING; v. 11, n. 549, p. 12-pg., 2018-09-25. |
| 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/EBP beta was attenuated by phosphorylation. To explain the mechanism of C/EBP recruitment, we solved the crystal structure of TRIB1 in complex with C/EBP alpha, which revealed that TRIB1 underwent a substantial conformational change relative to its substrate-free structure and bound C/EBP alpha 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 alpha C helix-and raise the possibility of small molecules targeting either the activation "loop-in" or "loop-out" conformations of Tribbles pseudokinases. (AU) | |
| FAPESP's process: | 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research |
| Grantee: | Paulo Arruda |
| Support Opportunities: | Research Grants - Research Partnership for Technological Innovation - PITE |