NIH HPC News & Announcements
Biowulf 25th Anniversary Seminar Series talk today 11am, Bldg 35A
Date: 18 April 2024 09:04:43
From: "Ulloa, Antonio [C]"
Please join us today for the first talk in the Biowulf 25th Anniversary Seminar Series:
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Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding
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Juliana Martinez Fiesco, Ph.D.
Center for Structural Biology
NCI-Frederick
Thursday, April 18, 2024
11am - noon
Building 35A Room 610 (First Floor)
Abstract:
The RAF kinases are key intermediates in the RAS pathway, functioning in the transmission of signals that regulate cell proliferation, differentiation, and survival. Under most signaling conditions binding to activated RAS is required for RAF dimerization and activation; however, the structural details for how RAS binding allows autoinhibited RAF monomers to assume an active dimer conformation has been unclear. We determined cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited, monomeric BRAF:14-3-32:MEK and BRAF:14-3-32 complexes, and an inhibitor-bound, dimeric BRAF2:14-3-32 complex. The autoinhibited BRAF structures show that prior to signaling events, BRAF and its substrate MEK can exist as a preassembled BRAF:14-3-32:MEK complex; however, the interaction with MEK is not required for BRAF to maintain the autoinhibited conformation. In the dimeric BRAF2:14-3-32 complex, both BRAF protomers are bound to an ATP-competitive BRAF inhibitor and the kinase domains assume the active conformation, suggesting the active sites of both protomers may bind ATP simultaneously to promote catalysis. In both autoinhibited, monomeric structures, the RAS binding domain (RBD) of BRAF is resolved, revealing the position and orientation of this critical domain, and providing insights regarding how RAS binding facilitates the monomer to dimer transition.
This talk will be videocast at: https://videocast.nih.gov/watch=54555
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