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Cell signalling

How monoubiquitylation keeps RAS active

Nature Reviews Molecular Cell Biology volume 14, pages 66–67 (2013)Cite this article

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The authors first developed a method in which RAS could be chemically linked to ubiquitin. They mutated Lys147 in RAS to Cys (RASK147C) and mutated a Gly residue at the carboxyl terminus of ubiquitin to Cys (ubiquitinG76C); a disulfide bond can form between these Cys residues and lead to monoubiquitylation of RASK147C by ubiquitinG76C. Computational models to compare RAS linked to ubiquitin by disulfide (chemical) and isopeptide (native) bonds confirmed that the chemical linkage efficiently mimics the native monoubiquitylation of RAS. Initial experiments using this system showed that monoubiquitylation at Lys147 does not alter the weak intrinsic GTPase activity of RAS, and therefore an alternative mechanism must promote the GTP-bound state of monoubiquitylated RAS.

monoubiquitylation at Lys147 activates RAS by reducing its sensitivity to GAPs

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References

ORIGINAL RESEARCH PAPER

  1. Baker, R. et al. Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function. Nature Struct. Mol. Biol. 25 Nov 2012 (doi:10.1038/nsmb.2430)

FURTHER READING

  1. Ahearn, I. M. et al. Regulating the regulator: post-translational modification of RAS. Nature Rev. Mol. Cell Biol. 13, 39–51 (2012)

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  1. Katharine H. Wrighton
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Wrighton, K. How monoubiquitylation keeps RAS active. Nat Rev Mol Cell Biol 14, 66–67 (2013). https://doi.org/10.1038/nrm3500

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