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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 α3 and α4 interface; H-Ras-GTP favours 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 favoured interactions of the HVRs (hypervariable regions) with cell membrane microdomains, biasing the effector-binding site orientations, thus isoform binding selectivity.

Original languageEnglish
Pages (from-to)1719-1732
Number of pages14
JournalBiochemical Journal
Issue number12
StatePublished - 15 Jun 2016


FundersFunder number
U.S. Government
National Institutes of HealthHHSN261200800001E
U.S. Department of Health and Human Services
National Cancer InstituteZIABC010441
Frederick National Laboratory for Cancer Research
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu114M196


    • HVR
    • K-Ras4B
    • Nanoclusters
    • Plasma membrane
    • Raf activation
    • Raf dimerization
    • Ras interfaces
    • Signalling.


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