Abstract
Neurabin is a brain-specific actin and protein phosphatase-1 (PP-1) binding protein that inhibits the purified catalytic subunit of protein phosphatase-1 (PP-1 C). However, endogenous PP-1 exists primarily as multimeric complexes of PP-1 C bound to various regulatory proteins that determine its activity, substrate specificity, subcellular localization and function. The major form of endogenous PP-1 in brain is protein phosphatase-1 I (PP-1 I), a Mg 2+/ATP-dependent form of PP-1 that consists of PP-1 C, the inhibitor-2 regulatory subunit, an activating protein kinase and other unidentified proteins. We have identified four PP-1 I holoenzyme fractions (PP-1 IA, PP-1 IB, PP-1 IC, and PP-1 ID) in freshly harvested pig brain separable by poly- l-lysine chromatography. Purified recombinant neurabin (amino acid residues 1–485) inhibited PP-1 IB (IC 50 = 1.1 μM), PP-1 IC (IC 50 = 0.1 μM), and PP-1 ID (IC 50 = 0.2 μM), but activated PP-1 IA by up to threefold (EC 50 = 40 nM). The PP-1 IA activation domain was localized to neurabin 1–210. Our results indicate a novel mechanism of PP-1 regulation by neurabin as both an inhibitor and an activator of distinct forms of PP-1 I in brain.
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