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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1

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Autor(es):
Jamieson, Sam A. [1] ; Ruan, Zheng [2] ; Burgess, Abigail E. [1] ; Curry, Jack R. [1] ; Mcmilan, Hamish D. [1] ; Brewster, Jodi L. [1] ; Dunbier, Anita K. [1] ; Axtman, Alison D. [3, 4] ; Kannan, Natarajan [2, 5] ; Mace, Peter D. [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Otago, Sch Biomed Sci, Biochem Dept, POB 56, 710 Cumberland St, Dunedin 9054 - New Zealand
[2] Univ Georgia, Inst Bioinformat, Athens, GA 30602 - USA
[3] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Struct Genom Consortium, Chapel Hill, NC 27599 - USA
[4] Univ North Carolina Chapel Hill, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 - USA
[5] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 - USA
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: Science Signaling; v. 11, n. 549 SEP 25 2018.
Citações Web of Science: 4
Resumo

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)

Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
Beneficiário:Paulo Arruda
Linha de fomento: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE