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Locking GTPases covalently in their functional states

Author

Listed:
  • David Wiegandt

    (Max Planck Institute of Molecular Physiology)

  • Sophie Vieweg

    (Max Planck Institute of Molecular Physiology)

  • Frank Hofmann

    (Max Planck Institute of Molecular Physiology)

  • Daniel Koch

    (Max Planck Institute of Molecular Physiology)

  • Fu Li

    (Max Planck Institute of Molecular Physiology
    Chemical Genomics Centre of the Max Planck Society)

  • Yao-Wen Wu

    (Max Planck Institute of Molecular Physiology
    Chemical Genomics Centre of the Max Planck Society)

  • Aymelt Itzen

    (Center for Integrated Protein Science Munich (CIPSM), Technische Universität München)

  • Matthias P. Müller

    (Max Planck Institute of Molecular Physiology)

  • Roger S. Goody

    (Max Planck Institute of Molecular Physiology)

Abstract

GTPases act as key regulators of many cellular processes by switching between active (GTP-bound) and inactive (GDP-bound) states. In many cases, understanding their mode of action has been aided by artificially stabilizing one of these states either by designing mutant proteins or by complexation with non-hydrolysable GTP analogues. Because of inherent disadvantages in these approaches, we have developed acryl-bearing GTP and GDP derivatives that can be covalently linked with strategically placed cysteines within the GTPase of interest. Binding studies with GTPase-interacting proteins and X-ray crystallography analysis demonstrate that the molecular properties of the covalent GTPase–acryl–nucleotide adducts are a faithful reflection of those of the corresponding native states and are advantageously permanently locked in a defined nucleotide (that is active or inactive) state. In a first application, in vivo experiments using covalently locked Rab5 variants provide new insights into the mechanism of correct intracellular localization of Rab proteins.

Suggested Citation

  • David Wiegandt & Sophie Vieweg & Frank Hofmann & Daniel Koch & Fu Li & Yao-Wen Wu & Aymelt Itzen & Matthias P. Müller & Roger S. Goody, 2015. "Locking GTPases covalently in their functional states," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8773
    DOI: 10.1038/ncomms8773
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