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J. Biol. Chem., Vol. 276, Issue 15, 12128-12134, April 13, 2001
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From the Howard Hughes Medical Institute, The phosphorylation status of cellular proteins
is controlled by the opposing actions of protein kinases and
phosphatases. Compartmentalization of these enzymes is critical for
spatial and temporal control of these phosphorylation/dephosphorylation events. We previously reported that a 220-kDa A-kinase anchoring protein (AKAP220) coordinates the location of the
cAMP-dependent protein kinase (PKA) and the type 1 protein
phosphatase catalytic subunit (PP1c) (Schillace, R. V., and Scott,
J. D. (1999) Curr. Biol. 9, 321-324). We now
demonstrate that an AKAP220 fragment is a competitive inhibitor of PP1c
activity (Ki = 2.9 ± 0.7 µM).
Mapping studies and activity measurements indicate that several
protein-protein interactions act synergistically to inhibit PP1. A
consensus targeting motif, between residues 1195 and 1198 (Lys-Val-Gln-Phe), binds but does not affect enzyme activity, whereas
determinants between residues 1711 and 1901 inhibit the phosphatase.
Analysis of truncated PP1c and chimeric PP1/2A catalytic subunits
suggests that AKAP220 inhibits the phosphatase in a manner distinct
from all known PP1 inhibitors and toxins. Intermolecular interactions
within the AKAP220 signaling complex further contribute to PP1
inhibition as addition of the PKA regulatory subunit (RII) enhances
phosphatase inhibition. These experiments indicate that regulation of
PP1 activity by AKAP220 involves a complex network of intra- and
intermolecular interactions.
Multiple Interactions within the AKAP220 Signaling Complex
Contribute to Protein Phosphatase 1 Regulation*
§,
Vollum
Institute, Oregon Health Sciences University,
Portland, Oregon 97201-3098, ¶ Department of Pharmacology and
Cancer Biology, Duke University Medical Center, Durham, North Carolina
27710, and the ** Discipline of Medical Biochemistry, School
of Biomedical Sciences, Faculty of Medicine and Health Sciences,
University of Newcastle, NSW, 2308, Australia
*
This work was supported by National Institutes of Health
Grants DK44239 (to J. D. S.) and DK52054 (to S. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Howard Hughes
Medical Institute, MRB 322 Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. Tel.:
503-494-4652; Fax: 503-494-0519; E-mail: scott@ohsu.edu.
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