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

作者：Jang Hyunbum; Muratcioglu Serena; Gursoy Attila; Keskin Ozlem; Nussinov Ruth

来源：Biochemical Journal, 2016, 473(12): 1719-1732.

DOI：10.1042/BCJ20160031

• HVR
• K-Ras4B
• nanoclusters
• Raf activation
• Raf dimerization
• Ras interfaces
• plasma membrane
• signalling

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 alpha 3 and alpha 4 interface; H-Ras-GTP favours alpha 4 and alpha 5. Both isoforms also populate a stable beta-sheet dimer interface formed by the effector lobe; a less stable beta-sandwich interface is sustained by salt bridges of the beta-sheet side chains. Raf's high-affinity beta-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.

• 出版日期2016-6-15