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Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK

Nature volume 399, pages 384–388 (1999)Cite this article

Abstract

The proteins Cdc42 and Rac are members of the Rho family of small GTPases (G proteins), which control signal-transduction pathways that lead to rearrangements of the cell cytoskeleton, cell differentiation and cell proliferation. They do so by binding to downstream effector proteins1. Some of these, known as CRIB (for Cdc42/Rac interactive-binding) proteins2, bind to both Cdc42 and Rac, such as the PAK1–3 serine/threonine kinases3, whereas others are specific for Cdc42, such as the ACK tyrosine kinases4,5 and the Wiscott–Aldrich-syndrome proteins (WASPs)6,7. The effector loop of Cdc42 and Rac (comprising residues 30–40, also called switch I), is one of two regions which change conformation on exchange of GDP for GTP. This region is almost identical in Cdc42 and Racs, indicating that it does not determine the specificity of these G proteins. Here we report the solution structure of the complex of Cdc42 with the GTPase-binding domain of ACK4,5. Both proteins undergo significant conformational changes on binding, to form a new type of G-protein/effector complex. The interaction extends the β-sheet in Cdc42 by binding an extended strand from ACK, as seen in Ras/effector interactions8,9, but it also involves other regions of the G protein that are important for determining the specificity of effector binding.

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Figure 1: Sequence comparisons, secondary structures and residues involved in complex formation.
Figure 2: Structure of the Cdc42/f–ACK complex.
Figure 3: The Cdc42/f-ACK interface.

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Acknowledgements

We thank M. Rudolph and A. Wittinghofer for the expression clone of the WASP Cdc42-binding domain; M. Nilges for X-PLOR scripts; M. Hirshberg for helpful comments on the manuscript; the MRC for a training fellowship (to H.R.M.) and the European Commission for financial support. The Cambridge Centre for Molecular Recognition is supported by the BBSRC and the Wellcome Trust.

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Author notes

  1. Helen R. Mott, Darerca Owen and Louis Lim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Cambridge Centre for Molecular Recognition, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK

    Helen R. Mott, Darerca Owen, Daniel Nietlispach & Ernest D. Laue

  2. Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Peter N. Lowe

  3. Institute of Molecular and Cell Biology, The National University of Singapore, 15 Lower Kent Ridge Road, 119076, Singapore

    Edward Manser & Louis Lim

  4. Institute of Neurology, 1 Wakefield Street, London, WC1N IPJ, UK

    Louis Lim

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  1. Helen R. Mott
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Correspondence to Ernest D. Laue.

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Mott, H., Owen, D., Nietlispach, D. et al. Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. Nature 399, 384–388 (1999). https://doi.org/10.1038/20732

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