Okadaic acid and microcystin insensitive PPP-family phosphatases may represent novel biotechnology targets

Abstract

R eversible protein phosphorylation is of central importance to the proper cellular functioning of all living organisms. Catalyzed by the opposing reactions of protein kinases and phosphatases, dysfunction in reversible protein phosphorylation can result in a wide variety of cellular aberrations. In eukaryotic organisms there exists four classes of protein phosphatases, of which the PPP-family protein phosphatases have documented susceptibility to a range of protein and small molecule inhibitors. These inhibitors have been of great importance to the biochemical characterization of PPP-family protein phosphatases since their discovery, but also maintain in natura biological significance with their endogenous regulatory properties (protein inhibitors) and toxicity (small molecule inhibitors). Recently, two unique PPP-family protein phosphatases, named the Shewanella-like protein phosphatases (SLP phosphatases), from Arabidopsis thaliana were characterized and found to be phylogenetically similar to the PPP-family protein phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), while completely lacking sensitivity to the classic PPP-family phosphatase small molecule inhibitors okadaic acid and microcystin-LR. SLP phosphatases were also found to be absent in metazoans, but present in a wide range of bacteria, fungi and protozoa responsible for human disease. The unique biochemical properties and evolutionary heritage of SLP phosphatases suggests they could not only be potential biotechnology targets for agriculture, but may also prove to be

Evolution of Bacterial-Like Phosphoprotein Phosphatases in Photosynthetic Eukaryotes Features Ancestral Mitochondrial or Archaeal Origin and Possible Lateral Gene Transfer

“…In PP1, for example, these interactions are mediated by small canonical motifs such as the RVxF and S/GILK motifs (Templeton et al, 2011). It has been recently suggested that SLP phosphatases might also interact with a diverse set of regulatory proteins (Uhrig and Moorhead, 2011b;Kutuzov and Andreeva, 2012). The data on C-terminal motifs presented here demonstrate that they maintain conserved class-specific alterations, which are most pronounced in photosynthetic eukaryotes (Figs.…”

“…This can include the development of healthier, disease-or stress-resistant crops in addition to treatments for parasitic organisms such as Plasmodium spp. (malaria; Patzewitz et al, 2013) and other chromoalveolates (Kutuzov and Andreeva, 2008;Uhrig and Moorhead, 2011b) that are derived from photosynthetic eukaryotes and maintain a remnant chloroplast (apicoplast; Le Corguillé et al, 2009;Janouskovec et al, 2010;Kalanon and McFadden, 2010;Walker et al, 2011). The existence of proteins that are conserved across diverse eukaryotic phyla but absent in metazoa, such as the majority of bacterial-like PPP protein phosphatases described here, presents unique research opportunities.…”

Protein Phosphatase-1 regulates Rift Valley fever virus replication

“…Traditional enzymatic PP1 inhibitors, such as okadaic acid or microcystien, are highly toxic and demonstrate poor selectivity as they inhibit both PP2A and PP1 33,34 . Okadaic acid has a strong preference for PP2A over PP1 33,34 .…”

“…Okadaic acid has a strong preference for PP2A over PP1 33,34 . We recently developed a PP1-targeting small molecule compound, 1E7-03 (Fig.…”

Oxidative Stress Parameters and Morphological Changes in Japanese Medaka (Oryzias latipes) after Acute Exposure to OA-Group Toxins

“…OA-group toxins are characterized by inhibiting serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) [ 14 , 15 , 16 ]. These inhibitions produce severe effects on intracellular processes such as metabolism, contractibility, inflammatory response, and maintenance of the cytoskeletal structure [ 17 , 18 , 19 ].…”