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Yeast Methionine Aminopeptidase Type 1 Is Ribosome-Associated and Requires Its N-Terminal Zinc Finger Domain for Normal Function in Vivo

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Yeast Methionine Aminopeptidase Type 1 Is Ribosome-Associated and Requires Its N-Terminal Zinc Finger Domain for Normal Function in Vivo Journal of Cellular Biochemistry 85:678–688 (2002) Yeast Methionine Aminopeptidase Type 1 Is Ribosome-Associated and Requires Its N-Terminal Zinc Finger Domain for Normal Function In Vivo Joseph A. Vetro and Yie-Hwa Chang* Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104 Abstract Methionine aminopeptidase type 1 (MetAP1) cotranslationally removes N-terminal methionine from nascent polypeptides, when the second residue in the primary structure is small and uncharged. Eukaryotic MetAP1 has an N-terminal zinc finger domain not found in prokaryotic MetAPs. We hypothesized that the zinc finger domain mediates the association of MetAP1 with the ribosomes and have reported genetic evidence that it is important for the normal function of MetAP1 in vivo. In this study, the intracellular role of the zinc finger domain in yeast MetAP1 function was examined. Wild-type MetAP1 expressed in a yeast map1 null strain removed 100% of N-terminal methionine from a reporter protein, while zinc finger mutants removed only 31–35%. Ribosome profiles of map1 null expressing wild-type MetAP1 or one of three zinc finger mutants were compared. Wild-type MetAP1 was found to be an 80S translational complex-associated protein that primarily associates with the 60S subunit. Deletion of the zinc finger domain did not significantly alter the ribosome profile distribution of MetAP1. In contrast, single point mutations in the first or second zinc finger motif disrupted association of MetAP1 with the 60S subunit and the 80S translational complex. Together, these results indicate that the zinc finger domain is essential for the normal processing function of MetAP1 in vivo and suggest that it may be important for the proper functional alignment of MetAP1 on the ribosomes. J. Cell. Biochem. 85: 678–688, 2002. ß 2002 Wiley-Liss, Inc. Key words: zinc finger; N-terminal protein processing; methionine aminopeptidase; ribosome association Eukaryotes initiate the translation of endoge- begin with an N-terminal methionine (Metinit). nous cytosolic mRNA with a methionine-bound Methionine aminopeptidase (MetAP, product of Met initiator tRNA (Met-tRNAi ) [Housman et al., the MAP gene, EC 3.4.11.18) cotranslationally 1972]. As a result, most nascent polypeptides removes Metinit from nascent polypeptides, when the second residue in the primary struc- ture is small and uncharged (e.g., Met–Ala–, – Cys–, –Gly–, –Pro–, –Ser–, –Thr–, –Val–) [Tsunasawa et al., 1985; Flinta et al., 1986; Abbreviations used: MetAP, methionine aminopeptidase; Ben-Bassat et al., 1987; Huang et al., 1987; map1D, yeast map1 deletion strain; GST, glutathione Boissel et al., 1988; Hirel et al., 1989; Moerschell S-transferase. et al., 1990]. Prokaryotes, as well as mitochon- Grant sponsor: American Cancer Society; Grant number: dria [Bianchetti et al., 1977] and chloroplasts RPG-99-155-01-CDD; Grant sponsor: American Heart [Lucchini and Bianchetti, 1980], initiate trans- Association (Predoctoral Fellowship to J.A.V.); Grant lation with an Na-formylated methionine bound number: 0010163Z. Met This article must be hereby marked ‘‘advertisement’’ in to an initiator tRNA (fMet-tRNAf ) [Clark and accordance with 18 U.S.C. section 1734 (as the cost of Marcker, 1966; Leder and Bursztyn, 1966; Noll, publication of this article was defrayed in part by the 1966]. MetAP requires deformylation of fMetinit payment of page charges). before Metinit can be removed [Adams, 1968; *Correspondence to: Yie-Hwa Chang, Edward A. Doisy Solbiati et al., 1999]. Department of Biochemistry and Molecular Biology, St. Louis University Health Sciences Center, 1402 S. MetAP activity is an essential cellular func- Grand Blvd., St. Louis, MO 63104. tion. Deletion of the single MAP gene in E. coli E-mail: [email protected] [Chang et al., 1989] and S. typhimurium [Miller Received 9 January 2002; Accepted 31 January 2002 et al., 1989] or of both MAP genes (MAP1 and DOI 10.1002/jcb.10161 MAP2) in yeast (S. cerevisiae) is lethal [Li and ß 2002 Wiley-Liss, Inc. Ribosomal Association of Yeast MetAP1 679 Chang, 1995]. Deletion of MAP1 [Chang et al., MetAP1 in vivo. We also examined the role of 1992] or MAP2 [Li and Chang, 1995] alone in the zinc finger domain in MetAP1 ribosome yeast results in a slow-growth phenotype. The association and found evidence that suggests map1 knockout strain (map1D), however, dis- it may be important for the correct functional plays a more severe slow-growth phenotype alignment of MetAP1 on the ribosomes. than the map2D strain [Li and Chang, 1995]. The more severe slow-growth phenotypeofyeast MATERIALS AND METHODS map1D correlates well with recent evidence Materials indicating that MetAP1 is primarily responsible for Metinit removal in yeast [Chen et al., 2002]. All chemicals were from Sigma (St. Louis, MO) Together, these data suggest that the growth unless otherwise stated. Two YPD reagents, rate of yeast correlates with the level of Metinit yeast extract and peptone, came from Difco. processing of proteins in vivo. Synthetic dropout media plus 2% dextrose (SD) Eukaryotic MetAPs, unlike prokaryotic contained yeast nitrogen base without amino MetAPs, possess an extended N-terminal region acids/ammonium sulfate (Difco) and were sup- [Arfin et al., 1995; Li and Chang, 1995]. Within plemented with amino acids to give the desired this N-terminal region, yeast MetAP1 has a zinc dropout mixture as described [Ausubel et al., finger domain [Chang et al., 1990] consisting of 1992]. DNA digests were carried out with a Cys2–Cys2 zinc finger motif (residues 22–40) restriction enzymes from Promega. similar to the RING finger family and a unique DNA Constructs Cys2–His2 (residues 50–66) motif similar to zinc fingers involved in RNA binding (IYC22SGLQC27- Construction of the MAP1 (wt) and zinc finger GRETSSQMKC37PVC40LKQGIVSIFC50DTSC54 mutants has been described [Zuo et al., 1995]. YENNYKAH62KALH66NAK) [Zuo et al., 1995]. Wild-type MAP1, a zinc finger domain deletion Furthermore, yeast MetAP1 chelates zinc in a mutant, map1 (D2-69), and two map1 zinc finger 2:1 molar ratio of zinc: MetAP1 and deletion of point mutants, map1 (C22S) and map1 (H62R), the putative N-terminal zinc finger domain were subcloned from pRS415 into pRS416 abolishes zinc binding [Zuo et al., 1995]. Thus, [Sikorski and Hieter, 1989] using Xho I/Sac I yeast MetAP1 is assumed to possess two func- for subsequent assay of MetAP1 activity in vivo. tional zinc fingers. A similar domain is found in Each construct is under 1 kb of the wild-type mammalian MetAP1 [Nagase et al., 1995] and MAP1 promoter. in plant MetAP1A from A. thaliana [Giglione Yeast/Bacteria Culturing and Transformations et al., 2000]. Zinc finger motifs have been reported to General handling and techniques for yeast mediate protein–protein and protein–nucleic and bacteria were followed as outlined [Ausubel acid interactions for a variety of proteins [Berg, et al., 1992]. Bacterial transformations were 1986; Struhl, 1989; Berg, 1990; Iuchi, 2001]. carried out using an E. coli transformation kit Thus, we proposed that the zinc finger do- (Zymo Research, Orange, CA) according to the main might mediate the presumed association manufacturer’s protocol. Yeast transformations of MetAP1 with the ribosomes [Jackson and were done by the alkali-cation method [Ito et al., Hunter, 1970; Chang et al., 1992]. 1983] using a yeast transformation kit (QBIO We have previously shown that the zinc finger Gene, Carlsbad, CA). domain is not required for MetAP1 catalytic Generation of Polyclonal Antibodies activity in vitro [Zuo et al., 1995]. However, unlike wild-type MetAP1, MetAP1 zinc finger A standard procedure was adapted [Harlow mutants cannot fully complement the slow- and Lane, 1988]. Oligopeptides corresponding growth phenotype of a yeast map1D strain to the amino acid sequence at the C-terminal [Zuo et al., 1995]. These findings suggest that end of the 40S subunit protein, RPS3 (CRPAE- the zinc finger domain is required for the normal ETEAQAEPVEA), the 60S subunit protein, function of MetAP1 within the cell. RPL3 (CAEKHAFMGTLKKDL), and MetAP2 In this report, we provide the first biochemical [Li and Chang, 1995] with an N-terminal cys- evidence of MetAP1 ribosome association and teine added for column coupling were obtained. present evidence that the zinc finger domain is Each peptide was conjugated to the carrier important for the normal processing function of protein maleimide-activated keyhole limpet 680 Vetro and Chang hemocyanin (KLH) at 2 mg peptide/2 mg KLH and L). Values are reported as the mean Æ SD% according to the manufacturer’s protocol (Pierce (n ¼ 4). Endogen). Each KLH-peptide immunogen was Ribosome Profiles of Yeast Crude Extracts mixed with an equal volume of Freund’s com- plete adjuvant, and 400 ml of the emulsion was Ribosome profiles of a yeast map1 (map1D) injected into each rabbit. Two booster injections knockout strain, YHC001 [Klinkenberg et al., of the same amount of antigen emulsified in 1997], singly transformed with yeast MAP1 (wt) incomplete Freund’s adjuvant were given at or map1 zinc finger mutants were performed weeks 4 and 8. Blood was collected from the ear with slight modifications [Eisinger et al., 1997]. prior to the initial injection and 10 days after A seed culture of each strain grown overnight in each boost. Blood samples were incubated at selective media was used to inoculate 300 ml room temperature 4 h before being placed at 48C SD/UraÀ. The culture was grown aerobically overnight. Coagulated blood was cleared by overnight at 308C to ABS600 1.0. Cultures centrifugation at 3,000g for 10 min. RPS3, were incubated on ice for 5 min after the RPL3, and MetAP2 polyclonal antibodies were addition of cycloheximide (100 mg/ml final con- purified using cyanogen bromide-activated thiol- centration) and harvested (5,000g,6min,48C, sepharose coupled with the respective peptide GS 3 rotor, Sorvall RC5C).
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