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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 remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. 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 subfamilies. 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.

Original publication

DOI

10.1016/j.jbc.2021.100521

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

01/2021

Volume

296

Addresses

Nuffield Department of Medicine, Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, Oxford, United Kingdom.

Keywords

GTP Phosphohydrolases, Catalytic Domain, Protein Conformation, Rho Guanine Nucleotide Exchange Factors