Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety.
Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety.
Sci Signal. 2020 Mar 31;13(625):
Authors: Grant BMM, Enomoto M, Back SI, Lee KY, Gebregiworgis T, Ishiyama N, Ikura M, Marshall CB
Abstract
KRAS4b is a small guanosine triphosphatase (GTPase) protein that regulates several signal transduction pathways that underlie cell proliferation, differentiation, and survival. KRAS4b function requires prenylation of its C terminus and recruitment to the plasma membrane, where KRAS4b activates effector proteins including the RAF family of kinases. The Ca2+-sensing protein calmodulin (CaM) has been suggested to regulate the localization of KRAS4b through direct, Ca2+-dependent interaction, but how CaM and KRAS4b functionally interact is controversial. Here, we determined a crystal structure, which was supported by solution nuclear magnetic resonance (NMR), that revealed the sequestration of the prenyl moiety of KRAS4b in the hydrophobic pocket of the C-terminal lobe of Ca2+-bound CaM. Our engineered fluorescence resonance energy transfer (FRET)-based biosensor probes (CaMeRAS) showed that, upon stimulation of Ca2+ influx by extracellular ligands, KRAS4b reversibly translocated in a Ca2+-CaM-dependent manner from the plasma membrane to the cytoplasm in live HeLa and HEK293 cells. These results reveal a mechanism underlying the inhibition of KRAS4b activity by Ca2+ signaling pathways.
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Source: Science Signaling - Category: Biomedical Science Authors: Grant BMM, Enomoto M, Back SI, Lee KY, Gebregiworgis T, Ishiyama N, Ikura M, Marshall CB Tags: Sci Signal Source Type: research