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Protein phosphatase 1 – targeted in many directions

Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD15EH, Scotland, UK

View larger version (16K): [in a new window]   Fig. 1. Schematic representation of several regulatory subunits of PP1 in higher eukaryotes. The RVxF PP1c-binding motif (dark blue) is immediately N-terminal to the ankyrin repeats in M110 and 53BP2. The RVxF motif in neurabin I and II precedes the PDZ domain but is not adjacent to it. Regions of weaker interactions with PP1c are indicated by a dark blue-line in GL, M110 and NIPP1 but may turn out to be smaller than indicated when fully documented. Weaker interaction sites have not been mapped for 53BP2 and neurabin I and may not have been fully mapped in other proteins. The Y335 site in NIPP1 may interact with PP1c independently of the RVxF motif. Some binding sites for I-2 (shown in turquoise) act independently of each other. Serine and threonine residues that alter the interaction with PP1c when phosphorylated are indicated (see Table 2). The allosteric binding site for phosphorylase a on GL is indicated. The binding regions for the protein or molecule that determines subcellular localization are shown in green. The binding site for myosin shown on M110 is that determined by Johnson et al. (Johnson et al., 1997) but the ankyrin repeat region might also bind to myosin (Hirano et al., 1997). The M21 subunit binds to the C-terminal region of M110. In the case of NIPP1, although RNA binds near the C-terminus, the region interacting with the splicing machinery is the FHA domain. All regulatory subunits are drawn to the same scale, M110 and I-1 being 1122 and 170 residues in length, respectively.

View larger version (41K): [in a new window]   Fig. 2. Structure of 53BP2 showing the site of interaction with PP1c. 53BP2 is represented as a ribbon structure on the basis of the crystal structure of 53BP2 (residues 796-1005) in complex with p53 (Gorina and Pavletich, 1996), which is available in the protein database at the NCBI. Residues 796GMRVKFN802 encompassing the RVxF motif at 798-801 (Helps et al., 1995) are mobile in the crystal and therefore not visible in the crystal structure. In the figure, Phe801 (depicted in red) and Asn802 have been added to the structure and illustrate that the position of the RVxF motif is highly exposed at the end of the ankyrin repeats (backbone indicated in green). The backbone of the SH3 domain of 53BP2 is indicated in purple.

View larger version (78K): [in a new window]   Fig. 3. Structure of the PP1c–RVxF-containing-peptide complex. PP1c is shown as a ribbon structure, and residues RRVSFA of the peptide are shown as green sticks with positively charged groups in blue and negatively charged groups in red. The GM peptide lies in a groove running parallel to the ß-strand ß14 (Leu289 –Leu296). The N-terminal arginine residue of the peptide is close to a negatively charged region that is likely to bind to other basic residues that are often found N-terminal to RRVxF. This negatively charged region on PP1c encompasses Glu54, Glu56, Asp166, and Glu67, which are involved in binding to the 12IKGI15 motif of I-2. The phosphate analogue tungstate is shown at the catalytic site. The ß12-ß13 loop containing Cys273 that covalently binds to microcystin is indicated in yellow. The figure was kindly produced by David Barford from the crystal structure of the PP1c-GM[63-75] peptide complex presented at the 1996 FASEB conference on protein phosphatases (Egloff et al., 1997).

View larger version (20K): [in a new window]   Fig. 4. Pathway by which insulin might stimulate glycogen synthesis through PP1 in the liver. Insulin is thought to activate cyclic-AMP phosphodiesterase, thereby lowering cyclic-AMP and leading to decreased levels of active phosphorylase (phosphorylase a). This relieves the phosphorylase a allosteric inhibition of GL-PP1c, increasing glycogen synthase phosphatase activity. Insulin also increases the levels of GL protein and mRNA.

View larger version (15K): [in a new window]   Fig. 5. Pathway by which smooth muscle contractility can be stimulated at constant Ca2+ levels. Agonists activating excitatory serpentine receptors coupled to heterotrimeric G-proteins, GTPS or arachidonic acid convert GDP-Rho-A to its GTP-bound form, which activates Rho-associated kinase. Phosphorylation of M110 on Thr697 by Rho-associated kinase leads to inhibition of M20-M110-PP1c activity, thereby increasing the phosphorylation of Ser19 on the regulatory myosin light chain in the absence of alterations in the Ca2+-dependent myosin light chain kinase activity. The pathway is blocked by Rho-associated kinase inhibitor Y27632. Contractility in non-muscle cells can be activated by lysophosphatidic acid through a similar pathway.

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