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Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors.

Publication ,  Journal Article
Connor, JH; Kleeman, T; Barik, S; Honkanen, RE; Shenolikar, S
Published in: J Biol Chem
August 6, 1999

Type-1 protein serine/threonine phosphatases (PP1) are uniquely inhibited by the mammalian proteins, inhibitor-1 (I-1), inhibitor-2 (I-2), and nuclear inhibitor of PP1 (NIPP-1). In addition, several natural compounds inhibit both PP1 and the type-2 phosphatase, PP2A. Deletion of C-terminal sequences that included the beta12-beta13 loop attenuated the inhibition of the resulting PP1alpha catalytic core by I-1, I-2, NIPP-1, and several toxins, including tautomycin, microcystin-LR, calyculin A, and okadaic acid. Substitution of C-terminal sequences from the PP2A catalytic subunit produced a chimeric enzyme, CRHM2, that was inhibited by toxins with dose-response characteristics of PP1 and not PP2A. However, CRHM2 was insensitive to the PP1-specific inhibitors, I-1, I-2, and NIPP-1. The anticancer compound, fostriecin, differed from other phosphatase inhibitors in that it inhibited wild-type PP1alpha, the PP1alpha catalytic core, and CRHM2 with identical IC(50). Binding of wild-type and mutant phosphatases to immobilized microcystin-LR, NIPP-1, and I-2 established that the beta12-beta13 loop was essential for the association of PP1 with toxins and the protein inhibitors. These studies point to the importance of the beta12-beta13 loop structure and conformation for the control of PP1 functions by toxins and endogenous proteins.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 6, 1999

Volume

274

Issue

32

Start / End Page

22366 / 22372

Location

United States

Related Subject Headings

  • Spiro Compounds
  • Sequence Homology, Amino Acid
  • Pyrones
  • Pyrans
  • Proteins
  • Protein Structure, Secondary
  • Protein Phosphatase 1
  • Protein Binding
  • Polyenes
  • Phosphoprotein Phosphatases
 

Citation

APA
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MLA
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Connor, J. H., Kleeman, T., Barik, S., Honkanen, R. E., & Shenolikar, S. (1999). Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors. J Biol Chem, 274(32), 22366–22372. https://doi.org/10.1074/jbc.274.32.22366
Connor, J. H., T. Kleeman, S. Barik, R. E. Honkanen, and S. Shenolikar. “Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors.J Biol Chem 274, no. 32 (August 6, 1999): 22366–72. https://doi.org/10.1074/jbc.274.32.22366.
Connor JH, Kleeman T, Barik S, Honkanen RE, Shenolikar S. Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors. J Biol Chem. 1999 Aug 6;274(32):22366–72.
Connor, J. H., et al. “Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors.J Biol Chem, vol. 274, no. 32, Aug. 1999, pp. 22366–72. Pubmed, doi:10.1074/jbc.274.32.22366.
Connor JH, Kleeman T, Barik S, Honkanen RE, Shenolikar S. Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors. J Biol Chem. 1999 Aug 6;274(32):22366–22372.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

August 6, 1999

Volume

274

Issue

32

Start / End Page

22366 / 22372

Location

United States

Related Subject Headings

  • Spiro Compounds
  • Sequence Homology, Amino Acid
  • Pyrones
  • Pyrans
  • Proteins
  • Protein Structure, Secondary
  • Protein Phosphatase 1
  • Protein Binding
  • Polyenes
  • Phosphoprotein Phosphatases