Ras membrane orientation and nanodomain localization generate isoform diversity

A1 Journal article (refereed)

Internal Authors/Editors

Publication Details

List of Authors: Abankwa D, Gorfe AA, Inder K, Hancock JF
Publication year: 2010
Journal: Proceedings of the National Academy of Sciences
Journal acronym: P NATL ACAD SCI USA
Volume number: 107
Issue number: 3
Start page: 1130
End page: 1135
Number of pages: 6
ISSN: 0027-8424


The structural elements encoding functional diversity among Ras GTPases are poorly defined. The orientation of the G domain of H-ras with respect to the plane of the plasma membrane is recognized by the Ras binding domain of C-Raf, coupling orientation to MAPK activation. We now show that two other proteins, phosphoinositide-3-kinase-alpha and the structurally unrelated galectin-1, also recognize G-domain orientation. These results rationalize the role of galectin-1 in generating active GTP-H-ras signaling nanoclusters. However, molecular dynamics simulations of K-ras membrane insertion and fluorescence lifetime imaging microscopy (FLIM)-Forster resonance energy transfer (FRET) imaging of the effector interactions of N-Ras, K-Ras, and M-ras suggest that there are two hyperactive, signaling-competent orientations of the Ras G domain. Mutational and functional analyses establish a clear relationship between effector binding and the amphilicities of helix alpha 4 and the C-terminal hypervariable region, thus confirming that these structural elements critically tune the orientation of the Ras G domain. Finally, we show that G-domain orientation and nanoclustering synergize to generate Ras isoform specificity with respect to effector interactions.


FRET, nanocluster, signal transduction, small G protein

Last updated on 2020-25-09 at 06:36