Structural and biophysical properties of farnesylated KRas interacting with the chaperone SmgGDS-558

GTPase splice variants RAC1 and RAC1B display isoform-specific differences in localization, prenylation, and interaction with the chaperone protein SmgGDS

“…SmgGDS-558 interacts with the PBR, prenyl group, and G-domain of RHOA ( 44 , 45 ). In contrast, we reported that SmgGDS-558 interacts with the PBR and prenyl group, but not the G-domain, of KRAS ( 50 ). Our finding that the WXXXN motif in SmgGDS-558 is critically involved in binding RAC1 and RAC1B, but not RHOA or KRAS ( Fig.…”

“…These different interactions have functional significance. The ability of SmgGDS to be a GEF for RHOA but not for KRAS or RAC1 ( 32 ) most likely occurs because SmgGDS engages the G-domain of RHOA but not KRAS or RAC1 ( 44 , 50 ). It is currently unknown if SmgGDS has GEF activity for RAC1B.…”

Biophysics of cancer

“…However, much remains to be learned about this hitherto elusive target whose mutations account for nearly a fifth of all human cancers. Pushing the frontier in this space are four papers that provide new insights into the organization of KRAS on the surface of model membranes alone (11) or in complex with another protein (12), its interaction with a chaperone protein (13), and its dynamics relative to its close homologs NRAS and HRAS (14). These studies are noteworthy not only because of their depth and sophistication but also because of the enormous amount of data they have analyzed.…”

“…For example, Ngo and Garcia have conducted atomistic molecular dynamics simulations in the millisecond timescale, a feat still only rarely achieved in the field (11). Moreover, the work of Nguyen et al (12) and Michalak et al (13) represents an excellent example of how to combine a state-of-the art simulation and spectroscopic techniques, such as NMR and surface plasmon resonance, to obtain richer information than is possible from one or a few techniques alone.…”