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J Biol Chem, Vol. 275, Issue 4, 2439-2446, January 28, 2000

Neurofilament-L Is a Protein Phosphatase-1-binding Protein Associated with Neuronal Plasma Membrane and Post-synaptic Density^*

Ryan T. Terry-Lorenzo^§, Masumi Inoue^¶, John H. Connor, Timothy A. J. Haystead, Blaine N. Armbruster, Ram P. Gupta, Carey J. Oliver^**, and Shirish Shenolikar

From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and the  Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908

Far Westerns with digoxigenin-conjugated protein phosphatase-1 (PP1) catalytic subunit identified PP1-binding proteins in extracts from bovine, rat, and human brain. A major 70-kDa PP1-binding protein was purified from bovine brain cortex plasma membranes, using affinity chromatography on the immobilized phosphatase inhibitor, microcystin-LR. Mixed peptide sequencing following cyanogen bromide digestion identified the 70-kDa membrane-bound PP1-binding protein as bovine neurofilament-L (NF-L). NF-L was the major PP1-binding protein in purified preparations of bovine spinal cord neurofilaments and the cytoskeletal compartment known as post-synaptic density, purified from rat brain cortex. Bovine neurofilaments, at nanomolar concentrations, inhibited the phosphorylase phosphatase activity of rabbit skeletal muscle PP1 catalytic subunit but not the activity of PP2A, another major serine/threonine phosphatase. PP1 binding to bovine NF-L was mapped to the head region. This was confirmed by both binding and inhibition of PP1 by recombinant human NF-L fragments. Together, these studies indicate that NF-L fulfills many of the biochemical criteria established for a PP1-targeting subunit and suggest that NF-L may target the functions of PP1 in membranes and cytoskeleton of mammalian neurons.

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^* This work was supported in part by National Institutes of Health Grants DK52054 (to S. S.) and HL19242 and DK52378A (to T. A. J. H.).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.

Both authors contributed equally to this manuscript.

^§ Supported by a National Science Foundation Graduate Research fellowship.

^¶ Present address: Dept. of Physiology, University of Fukuoka School of Medicine, Fukuoka, Japan.

^** Supported by Graduate Fellowship DAMD17-98-1-8705 from the Department of the Army.

To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710. Tel.: 919-681-6178; Fax: 919-681-9567; E-mail: sheno001@mc.duke.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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