Ras membrane orientation and nanodomain localization generate isoform diversity

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)

Interna författare/redaktörer

Publikationens författare: Abankwa D, Gorfe AA, Inder K, Hancock JF
Publiceringsår: 2010
Tidskrift: Proceedings of the National Academy of Sciences
Tidskriftsakronym: P NATL ACAD SCI USA
Volym: 107
Nummer: 3
Artikelns första sida, sidnummer: 1130
Artikelns sista sida, sidnummer: 1135
Antal sidor: 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

Senast uppdaterad 2020-12-08 vid 04:22