Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 7, Pages 866-874Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.05.019
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Funding
- NHMRC (Australia) [569652, 511003]
- ARC (Australia) [DP1094080, LP0989954]
- Cancer Australia [631471]
- Australian Research Council [DP1094080] Funding Source: Australian Research Council
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Protein prenylation is required for membrane anchorage of small GTPases. Correct membrane targeting is essential for their biological activity. Signal output of the prenylated proto-oncogene Ras in addition critically depends on its organization into nanoscale proteolipid assemblies of the plasma membrane, so called nanoclusters. While protein prenylation is an established drug target, only a handful of nanoclustering inhibitors are known, partially due to the lack of appropriate assays to screen for such compounds. Here, we describe three cell-based high-throughput screening amenable Forster resonance energy transfer NANOclustering and Prenylation Sensors (NANOPS) that are specific for Ras, Rho, and Rab proteins. Rab-NANOPS provides the first evidence for nanoclustering of Rab proteins. Using NANOPS in a cell-based chemical screen, we now identify macrotetrolides, known ionophoric antibiotics, as submicromolar disruptors of Ras nanoclustering and MAPK signaling.
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