ABSTRACT Pseudokinases lack conservation of one or more of the catalytic residues in the kinase core and as a consequence are typically thought to be catalytically inactive. New work by Mukherjee et al. (2008) challenges this assumption. They show that the pseudokinase domain of CASK (Ca2+/calmodulin activated serine-threonine kinase) adopts an active conformation and displays catalytic activity in vivo.
Full-textDOI: · Available from: Kannan Natarajan, Aug 31, 2015
- SourceAvailable from: Krzysztof Pawłowski
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- "A large group of PKL proteins, lacking elements of the archetypical catalytic site, have been termed pseudokinases and believed to be inactive. However, these proteins are recently “being rethought” , . Examples appear of pseudokinases that retain some residual phosphorylation catalytic capability despite an “incapacitated” active site, like Erbb3, a disabled kinase with residual activity lacking the “essential” HRD motif. "
ABSTRACT: Selenoproteins serve important functions in many organisms, usually providing essential oxidoreductase enzymatic activity, often for defense against toxic xenobiotic substances. Most eukaryotic genomes possess a small number of these proteins, usually not more than 20. Selenoproteins belong to various structural classes, often related to oxidoreductase function, yet a few of them are completely uncharacterised. Here, the structural and functional prediction for the uncharacterised selenoprotein O (SELO) is presented. Using bioinformatics tools, we predict that SELO protein adopts a three-dimensional fold similar to protein kinases. Furthermore, we argue that despite the lack of conservation of the “classic” catalytic aspartate residue of the archetypical His-Arg-Asp motif, SELO kinases might have retained catalytic phosphotransferase activity, albeit with an atypical active site. Lastly, the role of the selenocysteine residue is considered and the possibility of an oxidoreductase-regulated kinase function for SELO is discussed. The novel kinase prediction is discussed in the context of functional data on SELO orthologues in model organisms, FMP40 a.k.a.YPL222W (yeast), and ydiU (bacteria). Expression data from bacteria and yeast suggest a role in oxidative stress response. Analysis of genomic neighbourhoods of SELO homologues in the three domains of life points toward a role in regulation of ABC transport, in oxidative stress response, or in basic metabolism regulation. Among bacteria possessing SELO homologues, there is a significant over-representation of aquatic organisms, also of aerobic ones. The selenocysteine residue in SELO proteins occurs only in few members of this protein family, including proteins from Metazoa, and few small eukaryotes (Ostreococcus, stramenopiles). It is also demonstrated that enterobacterial mchC proteins involved in maturation of bactericidal antibiotics, microcins, form a distant subfamily of the SELO proteins. The new protein structural domain, with a putative kinase function assigned, expands the known kinome and deserves experimental determination of its biological role within the cell-signaling network.PLoS ONE 02/2012; 7(2):e32138. DOI:10.1371/journal.pone.0032138 · 3.23 Impact Factor
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- "This is mainly due to an expansion of the Tox - oplasma - specific ROPK family , consisting of $ 44 genes of which approximately half are pseudokinases . It must be considered in this context that some proteins thought to be pseudokinases on the basis of their sequence characteristics were actually shown to be competent for phosphorylation ( Kannan and Taylor , 2008 ; Taylor and Kornev , 2010 ) . This may be particularly relevant to se - quences that are relatively distant from classical ePKs , such as the ROPKs and FIKKs ( see below ) . "
ABSTRACT: Some apicomplexan parasites have evolved distinct protein kinase families to modulate host cell structure and function. Toxoplasma gondii rhoptry protein kinases and pseudokinases are involved in virulence and modulation of host cell signalling. The proteome of Plasmodium falciparum contains a family of putative kinases called FIKKs, some of which are exported to the host red blood cell and might play a role in erythrocyte remodelling. In this review we will discuss kinases known to be critical for host cell invasion, intracellular growth and egress, focusing on (i) calcium-dependent protein kinases and (ii) the secreted kinases that are unique to Toxoplasma (rhoptry protein kinases and pseudokinases) and Plasmodium (FIKKs).International journal for parasitology 12/2011; 42(1):21-32. DOI:10.1016/j.ijpara.2011.11.007 · 3.40 Impact Factor
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- "Recent structure-function analyses of other “pseudokinases”, such as CASK  and haspin , which have atypical kinase domains similar to ILK, have clearly demonstrated that atypical kinase domains can be functional and are capable of catalysis. Novel mechanisms for kinase activity have been identified through these structure-function analyses , . The structure of the ILK kinase domain has recently been solved, albeit as a complex with α-parvin, resulting in an inactive conformation and demonstrating that this domain of ILK can form a bi-lobed kinase-like conformation and can bind ATP, but can also function as a protein scaffold. "
ABSTRACT: Background Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.Methodology/Principal FindingsHere, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3) peptide and the 20-kDa regulatory light chains of myosin (LC20). Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP-binding lysine (K220 within subdomain 2) causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the Km for MnATP is ∼150-fold less than that for MgATP).Conclusions/SignificanceTaken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases.PLoS ONE 08/2010; 5(8). DOI:10.1371/journal.pone.0012356 · 3.23 Impact Factor