Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers.

Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov

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.