6XAG

Apo BRAF dimer bound to 14-3-3

Summary for 6XAG

• Entry DOI: 10.2210/pdb6xag/pdb
• Descriptor: 14-3-3 protein zeta/delta, Serine/threonine-protein kinase B-raf, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: kinase, signaling protein, signaling protein-transferase complex, signaling protein/transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 119157.55

Authors

Liau, N.P.D.,Hymowitz, S.G.,Sudhamsu, J. (deposition date: 2020-06-04, release date: 2020-10-07, Last modification date: 2024-10-23)

Primary citation

Liau, N.P.D.,Venkatanarayan, A.,Quinn, J.G.,Phung, W.,Malek, S.,Hymowitz, S.G.,Sudhamsu, J.
Dimerization Induced by C-Terminal 14-3-3 Binding Is Sufficient for BRAF Kinase Activation.
Biochemistry, 59:3982-3992, 2020

PubMed Abstract: 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.

PubMed: 32970425
DOI: 10.1021/acs.biochem.0c00517

Experimental method

X-RAY DIFFRACTION (3.3 Å)