The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodelling, playing roles in various crucial processes such as differentiation, migration, polarisation and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process which is otherwise too slow for rapid spatiotemporal control of cellular signalling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK sub-families. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes.
The Journal of biological chemistry
Alzheimer's Research UK Oxford Drug Discovery Institute, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, United Kingdom; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, United Kingdom; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, OX3 7DQ, United Kingdom.