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Tyrosine Hydroxylase Purification from Rat PC1 2 Ceils

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Tyrosine Hydroxylase Purification from Rat PC1 2 Ceils PROTEIN EXPRESSION AND PURIFICATION 2, 10-14 (19%) Tyrosine Hydroxylase Purification from Rat PC1 2 Ceils Laura G. Gahn and Robert Roskoski, Jr. Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, Louisiana 70119 Received January 25,199l of tyrosine hydroxylase and has been used to purify Tyrosine hydroxylase was purified in high yield from small amounts (240-300 pug) of the enzyme (12,13). We rat PC12 cells. This three-day procedure consisted of report here a protocol for the purification of about 15 differential ammonium sulfate precipitation, anion-ex- mg of homogeneous, stable rat tyrosine hydroxylase in change chromatography, and heparin-Sepharose affin- high yield from PC12 cells in culture. ity chromatography. It yielded an average of I5 mg of purified protein from 100 flasks of PC12 cells, with MATERIALS AND METHODS greater than 40% recovery of tyrosine hydroxylase. So- dium dodecyl sulfate-polyacrylamide gel electrophore- Materials sis yielded a single protein band with a molecular Catalase, tyrosine, piperazine-2\r,iV’-bis(2-ethanesul- weight of approximately 60,000. The protein had a spe- fonic acid) (Pipes), tris(hydroxymethyl)aminomethane, cific activity of 670 nmollminlmg and had a K,,, for its KCl, and dithiothreitol were obtained from Sigma reducing .cofactor tetrahydrobiopterin of 1.8 mM. The Chemical Co. (St. Louis, MO). Ammonium sulfate, po- purified protein can be phosphorylated and activated tassium phosphate, NaCl, HCl, MgCl,, and decolorizing by cyclic AMP-dependent protein kinase. o 1991 Academic carbon (Darco G-60) were obtained from J. T. Baker Press, Inc. (Jackson, TN). RPM1 1640 and gentamicin were from GIBCO (Grand Island, NY). Fetal calf serum and heat- inactivated horse serum were from Hazleton (Lenexa, Tyrosine hydroxylase (EC 1.14.16.2) catalyzes the KS). Sucrose was obtained from Bio-Rad (Richmond, rate-limiting step in catecholamine biosynthesis (1). It CA). L-[3,5-3H]Tyrosine was obtained from NEN Re- catalyzes the hydroxylation of tyrosine to form 3,4-di- search Products (Boston, MA). Diethylaminoethyl-cel- hydroxyphenylalanine (Dopa).’ The activity of this en- lulose (DE 52) was obtained from Whatman Biosystems zyme is regulated by many factors, including phosphor- (England) and heparin-Sepharose CL-6B was from ylation (2), salts (3), andpolyanions such as heparin (4). Pharmacia, Inc. (Piscataway, NJ). (6R)-5,6,7,8-Tetra- Studies of purified tyrosine hydroxylase have been hin- hydro-L-biopterin was obtained from Dr. B. Shircks dered by the difficulty in obtaining adequate amounts of Laboratories (Switzerland). purified enzyme. Published purification procedures re- port a yield of 0.2-2 mg of purified enzyme (5,6). Fur- Tyrosine Hydroxyluse Activity Assay thermore, purified tyrosine hydroxylase is reported to Tyrosine hydroxylase activity was assessed by mea- be unstable and to lose substantial activity in a matter suring the release of 3H,0 in the conversion of L-[3,5- of hours (7-9). The only large-scale purification of tyro- 3H]tyrosine to Dopa by the method of Reinhard et al. sine hydroxylase reported to date is that of the bovine (14). Enzyme (5-15 fig/ml) was incubated at 37°C with adrenal enzyme (lo), in which 17 mg of tyrosine hydrox- 100 PM L-[3,5-3H]tyrosine (0.5 &i per assay), 1 mM ylase was obtained from 2.5 kg of bovine adrenal me- (6R)-5,6,7,8-tetrahydro-L-biopterin, 1500 U/ml cata- dulla. The rat pheochromocytoma PC12 cell line estab- lase, 5 mM dithiothreitol, and 50 mM Pipes buffer (pH lished by Greene and Tischler (11) expresses high levels 6.0) in a total volume of 30 ~1. Samples were incubated for 10 min and the reaction was stopped by the addition of 300 ~17.5% charcoal (Darco G-60) in 1 N HCl. Char- * Abbreviations used: Dopa, 3,4-dihydroxyphenylalanine; Pipes, pi- perazine-N,N’-bis(2-ethanesulfonic acid); PMSF, phenylmethylsul- coal with adsorbed tyrosine and catechols was sedi- fonyl fluoride; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide mented by centrifugation at 13,000g for 2 min, aliquots gel electrophoresis. (100 ~1) of supernatant were removed, and 3H,0 radioac- 10 1046.5928/91 $3.00 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved. TYROSINEHYDROXYLASE FROM PC12CELLS 11 tivity was determined by liquid scintillation spectrome- at 40,OOOg for 60 min. To the supernatant, solid ammo- try. Samples were assayed in triplicate unless otherwise nium sulfate (30% saturation) was added over 20 min noted. The blank radioactivity (about 300 cpm) from with gentle stirring and the solution was stirred an addi- parallel samples containing water in place of enzyme tional 20 min. After centrifugation at 15,000g for 15 min, was subtracted from the sample values to yield net ac- the supernatant was collected. Additional ammonium tivity. sulfate was added to 42% saturation as described above and the precipitate was collected. The precipitate was then dissolved in buffer A and dialyzed against 100 vol Phosphorylation of Tyrosine Hydroxylase by Cyclic of the buffer overnight with one change of solution. The AMP-Dependent Protein Kinase Catalytic Subunit dialysate was then applied to a DEAE-cellulose column The catalytic subunit of cyclic AMP-dependent pro- (1.5 X 18 cm) equilibrated with Buffer A. The column tein kinase was purified by the method of Hart1 and was washed with 1 column vol of Buffer A, and tyrosine Roskoski (15). For phosphorylation, tyrosine hydroxy- hydroxylase was eluted with a linear gradient of 40-300 lase (250-500 pg/ml) was incubated in the presence of 1 mM NaCl in Buffer A (Fig. 1). The enzyme eluted at pM purified catalytic subunit (40,000 Da), 100 pM ATP, about 100 mM NaCl. The tyrosine hydroxylase-contain- and 1 mM MgCl, in 50 mM Pipes buffer (pH 6.0) at 30°C ing fractions were then pooled, ammonium sulfate was for 20 min. This procedure leads to the phosphorylation added to 44% saturation, and the precipitate was col- and activation of tyrosine hydroxylase (16). Control lected as described above. samples were incubated with MgCl, and buffer only. This precipitate was dissolved in 20 mM potassium The samples were diluted to provide a tyrosine hydroxy- phosphate (pH 7.4), 1 mM dithiothreitol, 5 pg/ml leu- lase concentration of 15 pg/ml during the assay. peptin, and 10 pM PMSF (Buffer B). Following over- night dialysis against 100 vol of Buffer B with one RESULTS change of solution, the dialysate was applied to a hepa- rin-Sepharose column (1 X 18 cm) equilibrated with Purification of Tyrosine Hydroxylase Buffer B. The column was then washed with Buffer B, Vulliet and co-workers (17) reported a procedure for 350 mM Tris-HCl in Buffer B, and Buffer B again. Tyro- the purification of 0.6 mg tyrosine hydroxylase from rat sine hydroxylase was not eluted from the column by pheochromocytoma. We have used a modification of Tris-HCl while other proteins were, so that the Tris- this procedure to purify tyrosine hydroxylase from HCl wash enhanced purification at this step (5). Tyro- PC12 cells. The cells were maintained in RPM1 1640 sine hydroxylase was eluted from the column with a lin- medium with 10% horse serum (heat inactivated), 5% ear gradient of 100-500 mM KC1 in Buffer B (Fig. l), fetal calf serum, and 50 pg/ml gentamicin in Nunc T175 with the enzyme eluting at approximately 250 mM KCl. flasks. Cells were kept at 37°C in a water-saturated, 5% The tyrosine hydroxylase-containing fractions were CO, atmosphere. Greene et al. (18) reported that the then pooled and concentrated by pressure dialysis cells attach poorly unless the culture flasks are colla- (Amicon stirred cell with Diaflo PM10 ultrafilter). For gen-coated. We found, however, that PC12 cells ad- PC12 enzyme preparations, the sample was stored in hered well to the Nunc flasks under these conditions. 0.5-ml aliquots of 0.4-2.5 mg/ml protein at -80°C in 5 Cultures were fed twice weekly by completely exchang- mM Tris-acetate (pH 8.2), 2 mM dithiothreitol, and 10% ing the medium. When confluent, the cells were either (w/v) sucrose until use. The resulting enzyme was stable subcultured or harvested by trituration, pelleted, and under these conditions for more than 2 years. Enzyme frozen at -80°C until use for tyrosine hydroxylase puri- was thawed prior to use and could be stored up to 6 fication. Cells were stored for 1 year with no loss of weeks at 2°C without appreciable loss of activity. There tyrosine hydroxylase activity. It is advisable to harvest was no loss of activity with up to four freeze-thaws, but confluent or near confluent cells for purification, since additional freeze-thaws were avoided. These prepara- cell-cell contact increases tyrosine hydroxylase expres- tions appear to be homogeneous as judged by visualiza- sion in PC12 cells (19). tion on sodium dodecyl sulfate-polyacrylamide gel elec- During the purification, all steps were performed at trophoresis (SDS-PAGE) with Coomassie blue staining 0-4°C. PMSF and leupeptin, protease inhibitors, were (Fig. 2). added to all solutions just before use. PC12 cells from Results from a typical purification cells are summa- 100 T175 flasks (30 ml of partially thawed, packed cells rized in Table 1. Total protein was assessed by the containing 1$2 g of protein, approximately 1 X lOlo method of Bradford (20) with bovine y-globulin as a cells) were homogenized with a polytron in 250 ml of 50 standard. Relative amounts of tyrosine hydroxylase mM potassium phosphate (pH 7.0), 7.5 mM mercap- were determined immunochemically by the method of toethanol, 1 mM EDTA, 5 pg/ml leupeptin, and 10 pM Haycock (21), using affinity-purified polyclonal rabbit phenylmethylsulfonyl fluoride (PMSF) (Buffer A) with antibodies to rat tyrosine hydroxylase and the purified 0.27 M sucrose.
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