Differential regulation of protein phosphatase-1(I) by neurabin.
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 microM), PP-1(IC) (IC(50)=0.1 microM), and PP-1(ID) (IC(50)=0.2 microM), 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.
Bullock
S Andrew
SA
Institute for Neuronal Cell Signaling, Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Platholi
Jimcy
J
Gjyrezi
Ada
A
Heerdt
Paul M
PM
Tung
H Y Lim
HY
Hemmings
Hugh C
HC
D000818:Animals; D001921:Brain / Q000201:enzymology; D020035:Holoenzymes / Q000378:metabolism; D008840:Microfilament Proteins / Q000494:pharmacology* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000494:pharmacology* / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D013552:Swine; D000099273:Neurabins
D020035:Holoenzymes; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D011994:Recombinant Proteins; D000099273:Neurabins