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

Authors:
Hyunbum Jang
Hyunbum Jang
National Cancer Institute
United States
Serena Muratcioglu
Serena Muratcioglu
Koc University
Turkey
Attila Gursoy
Attila Gursoy
Center for Computational Biology and Bioinformatics and College of Engineering
Ozlem Keskin
Ozlem Keskin
Koc University
Turkey
Ruth Nussinov
Ruth Nussinov
Frederick National Laboratory for Cancer Research
Frederick | United States

Biochem J 2016 06 7;473(12):1719-32. Epub 2016 Apr 7.

Cancer and Inflammation Program, National Cancer Institute at Frederick, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, U.S.A. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

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.

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http://dx.doi.org/10.1042/BCJ20160031DOI Listing
June 2016
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