New insights into Raf regulation from structural analyses |
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| Affiliation: | 1. Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA;2. California Institute for Quantitative Biosciences, University of California, Berkeley, CA, 94720, USA;3. The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada;4. Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA;5. Department of Chemistry, University of California, Berkeley, CA, 94720, USA;6. Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA |
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| Abstract: | BRAF is a highly regulated protein kinase that controls cell fate in animal cells. Recent structural analyses have revealed how active and inactive forms of BRAF bind to dimers of the scaffold protein 14-3-3. Inactive BRAF binds to 14-3-3 as a monomer and is held in an inactive conformation by interactions with ATP and the substrate kinase MEK, a striking example of enzyme inhibition by substrate binding. A change in the phosphorylation state of BRAF shifts the stoichiometry of the BRAF:14-3-3 complex from 1:2 to 2:2, resulting in stabilization of the active dimeric form of the kinase. These new findings uncover unexpected features of the regulatory mechanisms underlying Raf biology and help explain the paradoxical activation of Raf by small-molecule inhibitors. |
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