Dimerization Induced by C-Terminal 14–3–3 Binding Is Sufficient for BRAF Kinase Activation
| Autor: | Sarah G. Hymowitz, Jawahar Sudhamsu, John G. Quinn, Wilson Phung, Shiva Malek, Nicholas P. D. Liau, Avinashnarayan Venkatanarayan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Proto-Oncogene Proteins B-raf
endocrine system diseases Dimer Mutant Constitutively active Biochemistry Catalysis 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Tetramer Humans neoplasms 0303 health sciences Kinase 030302 biochemistry & molecular biology Raf kinase digestive system diseases Cell biology BRAF V600E enzymes and coenzymes (carbohydrates) 14-3-3 Proteins chemistry Phosphorylation Protein Multimerization Protein Binding Signal Transduction |
| Zdroj: | Biochemistry. 59:3982-3992 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | The Ras-RAF-MEK-ERK signaling axis, commonly mutated in human cancers, is highly regulated to prevent aberrant signaling in healthy cells. One of the pathway modulators, 14-3-3, a constitutive dimer, induces RAF dimerization and activation by binding to a phosphorylated motif C-terminal to the RAF kinase domain. Recent work has suggested that a C-terminal "DTS" region in BRAF is necessary for this 14-3-3-mediated activation. We show that the catalytic activity and ATP binding affinity of the BRAF:14-3-3 complex is insensitive to the presence or absence of the DTS, while the ATP sites of both BRAF molecules are identical and available for binding. We also present a crystal structure of the apo BRAF:14-3-3 complex showing that the DTS is not required to attain the catalytically active conformation of BRAF. Rather, BRAF dimerization induced by 14-3-3 is the key step in activation, allowing the active BRAF:14-3-3 tetramer to achieve catalytic activity comparable to the constitutively active oncogenic BRAF V600E mutant. |
| Databáze: | OpenAIRE |
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