Abstract

Reversible protein serine/threonine phosphorylation is an important component of the intracellular signaling machinery. It regulates many of the process such as neurotransmission, muscle contraction, glycogen synthesis, T-cell activation, neuronal plasticity and cell proliferation (Aggen et.al., 2000). Protein serine/threonine phosphatases are divided into three structurally unrelated families. The PPM family comprises Mg2+-dependent enzymes, including protein phosphatase 2C (PP2C). The FCP family contains only one member, which is also Mg2+ dependent. All other protein serine/threonine phosphatases are classified in the PPP family, consisting of the subfamilies PP1, PP2A (including PP4 and PP6), PP2B, and PP5, all having a structurally related core and a similar catalytic mechanism (Ceulemans H and Bollen M, 2003).

In eukaryotes PP1 exists in a large number of isoforms. In humans PP1 is encoded by three highly related genes (PP1 alpha, PP1 beta/delta and PP1 gamma), and alternative splicing generates the gamma1 and gamma2 isoforms. While Saccharomyces cerevisiae is an exception, with only one PP1 gene (glc7), many eukaryotes have multiple PP1 genes - 8 in Arabidopsis thaliana, 4 in Drosophila melanogaster and a predicted 30 in Caenorhabditis elegans (Moorhead et.al., 2007). The function of all these isoforms are presently unclear.



The regulatory subunits recruit active PP1c to dephosphorylate phosphothreonine or phosphoserine residues in the target substrates. Three grooves (hydrophobic, C-terminal, and acidic) have been defined on the surface of PP1 (James et.al., 2001). The hydrophobic groove of PP1c interacts with the RVXF motif in the regulatory proteins. The RVXF peptide backbone binds by beta-augmentation within the hydrophobic patch. So far more than 90 regulatory protein of PP1 with this characterised motif are documented (Moorhead et.al., 2007). These mostly mediate substrate target selection but some are inhibitors of PP1 for example phospho-DARPP-32.