Abstract
Pseudoenzymes are emerging as significant mediators and regulators of signal transduction. These proteins maintain enzyme folds and topologies, but are disrupted in the conserved motifs required for enzymatic activity. Among the pseudoenzymes, the pseudoGTPase group of atypical GTPases has recently expanded and includes the Rnd and RGK groups, RhoH and the RhoBTB proteins, mitochondrial RhoGTPase and centaurin-γ groups, CENP-M, dynein LIC, Entamoeba histolytica RabX3, leucine-rich repeat kinase 2, and the p190RhoGAP proteins. The wide range of cellular functions associated with pseudoGTPases includes cell migration and adhesion, membrane trafficking and cargo transport, mitosis, mitochondrial activity, transcriptional control, and autophagy, placing the group in an expanding portfolio of signaling pathways. In this review, we examine how the pseudoGTPases differ from canonical GTPases and consider their mechanistic and functional roles in signal transduction. We review the amino acid differences between the pseudoGTPases and discuss how these proteins can be classified based on their ability to bind nucleotide and their enzymatic activity. We discuss the molecular and structural consequences of amino acid divergence from canonical GTPases and use comparison with the well-studied pseudokinases to illustrate the classifications. PseudoGTPases are fast becoming recognized as important mechanistic components in a range of cellular roles, and we provide a concise discussion of the currently identified members of this group. ENZYMES: small GTPases; EC number: EC 3.6.5.2.