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PseudoGTPase domains in p190RhoGAP proteins: a mini-review.

Published on Dec 17, 2018in Biochemical Society Transactions4.291
· DOI :10.1042/BST20180481
Amy L. Stiegler11
Estimated H-index: 11
(Yale University),
Titus J. Boggon48
Estimated H-index: 48
(Yale University)
Abstract
Pseudoenzymes generally lack detectable catalytic activity despite adopting the overall protein fold of their catalytically competent counterparts, indeed ‘pseudo’ family members seem to be incorporated in all enzyme classes. The small GTPase enzymes are important signaling proteins, and recent studies have identified many new family members with noncanonical residues within the catalytic cleft, termed pseudoGTPases. To illustrate recent discoveries in the field, we use the p190RhoGAP proteins as an example. p190RhoGAP proteins ( ARHGAP5 and ARHGAP35 ) are the most abundant GTPase activating proteins for the Rho family of small GTPases. These are key regulators of Rho signaling in processes such as cell migration, adhesion and cytokinesis. Structural biology has complemented and guided biochemical analyses for these proteins and has allowed discovery of two cryptic pseudoGTPase domains, and the re-classification of a third, previously identified, GTPase-fold domain as a pseudoGTPase. The three domains within p190RhoGAP proteins illustrate the diversity of this rapidly expanding pseudoGTPase group.
  • References (56)
  • Citations (3)
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References56
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#1Amy L. Stiegler (Yale University)H-Index: 11
#2Titus J. Boggon (Yale University)H-Index: 48
Summary The pseudoGTPases are a rapidly growing and important group of pseudoenzymes. p190RhoGAP proteins are critical regulators of Rho signaling and contain two previously identified pseudoGTPase domains. Here we report that p190RhoGAP proteins contain a third pseudoGTPase domain, termed N-GTPase. We find that GTP constitutively purifies with the N-GTPase domain, and a 2.8-A crystal structure of p190RhoGAP-A co-purified with GTP reveals an unusual GTP-Mg 2+ binding pocket. Six inserts in N-GTP...
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Summary The pseudo-kinase and signaling protein Pragmin has been linked to cancer by regulating protein tyrosine phosphorylation via unknown mechanisms. Here we present the crystal structure of the Pragmin 906–1,368 amino acid C terminus, which encompasses its kinase domain. We show that Pragmin contains a classical protein-kinase fold devoid of catalytic activity, despite a conserved catalytic lysine (K997). By proteomics, we discovered that this pseudo-kinase uses the tyrosine kinase CSK to in...
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: The pseudokinase group encompasses some 10% of protein kinases, but pseudokinases diverge from canonical kinases in key motifs. The two members of the small new kinase family 3 (NKF3) group are considered pseudokinases. These proteins, pseudopodium-enriched atypical kinase 1 (PEAK1, Sugen kinase 269, or SgK269) and pragmin (Sugen kinase 223 or SgK223), act as scaffolds in growth factor signaling pathways, and both contain a kinase fold with degraded kinase motifs at their C termini. These kina...
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#1James M. Murphy (University of Melbourne)H-Index: 39
#2Peter D. Mace (University of Otago)H-Index: 21
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Pseudoenzymes were first described more than 50 years ago, when it was recognised that a subset of proteins that are structurally homologous to active enzymes lack amino acids necessary for catalytic activity. Recently, interest in pseudoenzymes has surged as it has become apparent that they constitute ∼10% of proteomes and perform essential metabolic and signalling functions that can be experimentally distinguished from catalytic outputs of enzymes. Here, we highlight recent structural studies ...
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#1Amy L. Stiegler (Yale University)H-Index: 11
#2Titus J. Boggon (Yale University)H-Index: 48
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Pseudoenzymes are catalytically dead counterparts of enzymes. Despite their first description some 50 years ago, the importance and functional diversity of these ‘fit-for-purpose’ polypeptides is only now being appreciated. Pseudoenzymes have been identified throughout all the kingdoms of life and, owing to predicted deficits in enzyme activity due to the absence of catalytic residues, have been variously referred to as pseudoenzymes, non-enzymes, dead enzymes, prozymes or ‘zombie’ proteins. An ...
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The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles ...
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