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Structure of Cdc42 bound to the GTPase binding domain of PAK

Nature Structural Biology volume 7, pages 384–388 (2000)Cite this article

Abstract

The Rho family GTPases, Cdc42, Rac and Rho, regulate signal transduction pathways via interactions with downstream effector proteins. We report here the solution structure of Cdc42 bound to the GTPase binding domain of αPAK, an effector of both Cdc42 and Rac. The structure is compared with those of Cdc42 bound to similar fragments of ACK and WASP, two effector proteins that bind only to Cdc42. The N-termini of all three effector fragments bind in an extended conformation to strand β2 of Cdc42, and contact helices α1 and α5. The remaining residues bind to switches I and II of Cdc42, but in a significantly different manner. The structure, together with mutagenesis data, suggests reasons for the specificity of these interactions and provides insight into the mechanism of PAK activation.

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Figure 1: Sequence comparisons.
Figure 2: Structure of free and bound PAK.
Figure 3: Close up stereo views of the Cdc42–PAK interface showing side chains of key residues involved in the interaction.
Figure 4: Comparison of the structures of

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Acknowledgements

We thank G. Thompson for the PAK(75–118) clone. A.M. is supported by a CASE award from the Medical Research Council and Glaxo-Wellcome. M.V. is supported by a grant from the Cambridge Commonwealth Trust (Cambridge Nehru Scholarship) and an Overseas Research Students (ORS) award. H.R.M. is an MRC Training Fellow. We acknowledge The European Commission for financial support. The Cambridge Centre for Molecular Recognition and the National 800 Facility are supported by the BBSRC and the Wellcome Trust.

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Authors and Affiliations

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

    Angela Morreale, Meenakshi Venkatesan, Helen R. Mott, Darerca Owen, Daniel Nietlispach & Ernest D. Laue

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

    Peter N. Lowe

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  1. Angela Morreale
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Correspondence to Ernest D. Laue.

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Morreale, A., Venkatesan, M., Mott, H. et al. Structure of Cdc42 bound to the GTPase binding domain of PAK. Nat Struct Mol Biol 7, 384–388 (2000). https://doi.org/10.1038/75158

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