Are the dimer structures of active Ras isoforms similar? This question is significant since Ras can activate its effectors as a monomer; however, as a dimer it promotes Raf's activation and MAPK cell signaling. Here, we model possible catalytic domain dimer interfaces of membrane-anchored GTP-bound K-Ras4B and H-Ras, and compare their conformations. The active helical dimers formed by the allosteric lobe are isoform-specific: K-Ras4B-GTP favors the α3 and α4 interface; H-Ras-GTP favors α4 and α5. Both isoforms also populate a stable β-sheet dimer interface formed by the effector lobe; a less stable β-sandwich interface is sustained by salt-bridges of the β-sheet side-chains. Raf's high affinity β-sheet interaction is promoted by the active helical interface. Collectively, Ras isoforms' dimer conformations are not uniform; instead, the isoform-specific dimers reflect the favored interactions of the hypervariable regions (HVRs) with cell membrane microdomains, biasing the effector binding site orientations - thus isoform binding selectivity.
- Raf dimerization
- Raf activation
- Ras interfaces
- ©2016 The Author(s)
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