A dock and coalesce mechanism driven by hydrophobic interactions governs Cdc42 binding with its effector protein ACK
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology Inc.
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Owen, D., Mott, H., Tetley, G., & Cooley, R. (2017). A dock and coalesce mechanism driven by hydrophobic interactions governs Cdc42 binding with its effector protein ACK. Journal of Biological Chemistry, 292 11361-11373. https://doi.org/10.1074/jbc.M117.789883
Cdc42 is a Rho-family small G protein that has been widely studied for its role in controlling the actin cytoskeleton and plays a part in several potentially oncogenic signalling networks. Similar to most other small G proteins, Cdc42 binds to many downstream effector proteins to elicit its cellular effects. These effector proteins all engage the same face of Cdc42, the conformation of which is governed by the activation state of the G protein. Previously, the importance of individual residues in conferring binding affinity has been explored for residues within Cdc42 for three of its CRIB effectors, activated Cdc42 kinase (ACK), p21-activated kinase (PAK), and Wiskott-Aldrich syndrome protein (WASP). Here, in a complementary study, we have used our structure of Cdc42 bound to ACK via an intrinsically disordered ACK region, to guide an analysis of the Cdc42 interface on ACK, creating a panel of mutant proteins with which we can now describe the complete energetic landscape of the Cdc42-binding site on ACK. Our data suggest that the binding affinity of ACK relies on several conserved residues that are critical for stabilizing the quaternary structure. These residues are centred on the CRIB region, with the complete binding region anchored at each end by hydrophobic interactions. These findings suggest that ACK adopts a dock and coalesce binding mechanism with Cdc42. In contrast to other CRIB-family effectors and indeed other intrinsically disordered proteins, hydrophobic residues likely drive Cdc42-ACK binding.
CDC42, cell signalling, G protein, intrinsically disordered protein, protein conformation, protein motif, protein structure, protein-protein interaction, small GTPase, tyrosine kinase
This research was supported by an MRC CASE Studentship (MR/K017101/1) to DO, HRM and RNC.
External DOI: https://doi.org/10.1074/jbc.M117.789883
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264658
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/