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

ABSTRACT: 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 (mitogen-activated protein kinase) cell signalling. In the present study, 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 favours the ?3 and ?4 interface; H-Ras-GTP favours ?4 and ?5. Both isoforms also populate a stable ?-sheet dimer interface formed by the effector lobe; a less stable ?-sandwich interface is sustained by salt bridges of the ?-sheet side chains. Raf's high-affinity ?-sheet interaction is promoted by the active helical interface. Collectively, Ras isoforms' dimer conformations are not uniform; instead, the isoform-specific dimers reflect the favoured interactions of the HVRs (hypervariable regions) with cell membrane microdomains, biasing the effector-binding site orientations, thus isoform binding selectivity.

SUBMITTER: Jang H 

PROVIDER: S-EPMC7830773 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature