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A Metallothionein Containing a Zinc Finger Within a Four-Metal Cluster Protects a Bacterium from Zinc Toxicity

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A Metallothionein Containing a Zinc Finger Within a Four-Metal Cluster Protects a Bacterium from Zinc Toxicity A metallothionein containing a zinc finger within a four-metal cluster protects a bacterium from zinc toxicity Claudia A. Blindauer*, Mark D. Harrison†, John A. Parkinson*, Andrea K. Robinson†, Jennifer S. Cavet†, Nigel J. Robinson†‡, and Peter J. Sadler*‡ *Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom; and †Department of Biochemistry and Genetics, University of Newcastle, Newcastle NE2 4HH, United Kingdom Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved June 19, 2001 (received for review March 12, 2001) Zinc is essential for many cellular processes, including DNA synthesis, His residues, which have been implicated in metal coordination transcription, and translation, but excess can be toxic. A zinc-induced (14). The Cys coordination pattern for the MT clusters cannot be gene, smtA, is required for normal zinc-tolerance in the cyanobacte- mapped onto the sequence of SmtA. Genome sequences have rium Synechococcus PCC 7942. Here we report that the protein SmtA recently revealed smtA-related genes in several bacteria, including contains a cleft lined with Cys-sulfur and His-imidazole ligands that pathogens, and we previously detected an MT-like protein in binds four zinc ions in a Zn4Cys9His2 cluster. The thiolate sulfurs of five Pseudomonas putida from a metal-polluted site (15). To investigate Cys ligands provide bridges between the two ZnCys4 and two the analogy between SmtA and MT, and to understand better how ZnCys3His sites, giving two fused six-membered rings with distorted bacterial MTs buffer excess heavy metals, we have determined the boat conformations. The inorganic core strongly resembles the solution structure of SmtA and investigated its metal uptake and Zn4Cys11 cluster of mammalian metallothionein, despite different exchange behavior. amino acid sequences, a different linear order of the ligands, and presence of histidine ligands. Also, SmtA contains elements of sec- Materials and Methods ondary structure not found in metallothioneins. One of the two Protein Expression and Purification. To express SmtA in E. coli,an BIOCHEMISTRY Cys4-coordinated zinc ions in SmtA readily exchanges with exoge- NdeI restriction site was introduced at the 5Ј end of the SmtA nous metal (111Cd), whereas the other is inert. The thiolate sulfur coding region in pMDNR1.1 (14) by using Quik-change mutagen- ligands bound to zinc in this site are buried within the protein. esis (Stratagene). The resulting NdeI͞BamHI fragment was sub- ␤ ␣ Regions of -strand and -helix surround the inert site to form a zinc cloned into pET29a (Novagen), creating pMHNR1.1. Aliquots (5 finger resembling the zinc fingers in GATA and LIM-domain proteins. ml) of cleared lysate from cells carrying pMHNR1.1 were applied Eukaryotic zinc fingers interact specifically with other proteins or DNA to a Sephadex G-50 column (2 ϫ 60 cm; Amersham Pharmacia) and an analogous interaction can therefore be anticipated for pro- equilibrated with 25 mM Tris (pH 8.8). Fractions containing SmtA karyotic zinc fingers. SmtA now provides structural proof for the were pooled and applied to a HiTrapQ column (1 ml; Amersham existence of zinc fingers in prokaryotes, and sequences related to the Pharmacia) equilibrated with 25 mM Tris (pH 8.8). SmtA was zinc finger motif can be identified in several bacterial genomes. eluted with a 40-ml 0–100 mM NaCl gradient. The purity of SmtA was confirmed by SDS͞PAGE and HPLC. N-terminal amino acid he cyanobacterium Synechococcus PCC 7942 synthesizes a sequencing showed that the protein began with TSTTL, indicating T56-aa cysteine-rich protein, SmtA, on exposure to elevated excision of the terminal Met in E. coli. 15N-labeled SmtA was concentrations of metals (Zn, Cd, and Cu; refs. 1 and 2). Zinc is the prepared from cells grown in minimal medium supplemented with 15 most potent inducer of transcription from the smtA operator NH4Cl-containing M9 salts. promoter, and repression of smtA in the absence of elevated zinc is 2ϩ mediated by the zinc-sensing, DNA-binding product of the diver- Preparation of Cd4SmtA. Homogeneous Cd -loaded SmtA was gently transcribed gene, smtB (3). Mutants lacking the smtA locus prepared by acidification of Zn4SmtA to pH 1 under nitrogen, are hypersensitive to elevated zinc (5-fold), but otherwise viable (4). separation of the apoprotein on a Sephadex G-25 column (pre- In addition to sequestering excess, it has been postulated that SmtA packed Amersham Pharmacia PD-10, equilibrated with 0.01 M may be involved in controlling the intracellular distribution of zinc HCl), and reconstitution in the presence of a slight excess of 111Cd2ϩ (5), but a specific partner (protein or DNA) for interaction with by raising the pH to 7.0 with Tris base (16). Excess Cd2ϩ was SmtA has not yet been identified. removed with Chelex-100 resin (Bio-Rad). SmtA has been classified as a bacterial metallothionein (MT), ⅐ although its sequence is very different from eukaryotic MTs. It is Zn–Cd Exchange. Zn4SmtA was incubated in 50 mM Tris HCl buffer unclear whether these proteins are in any way functionally analo- containing 50 mM NaCl (all reagents Fisher Scientific, analytical gous, because the function of neither has been fully defined. grade) for periods of6hto7days and at pH values from 5 to 8, at Metallothioneins are ubiquitous in eukaryotes and are small pro- teins containing about 60 amino acids (6). The solution structures of several vertebrate and invertebrate MTs have been determined This paper was submitted directly (Track II) to the PNAS office. by multidimensional NMR techniques (7). Such studies have pro- Abbreviations: ESI, electrospray ionization; ICP-AES, inductively coupled plasma–atomic vided the basis for understanding the dynamic behavior of MTs, emission spectrometry; NOE, nuclear Overhauser enhancement; NOESY, nuclear Over- especially of their metal ion uptake and release reactions. Mam- hauser enhancement spectroscopy; rmsd, rms deviation; amu, atomic mass unit; MT, metallothionein; HSQC, heteronuclear single quantum coherence. malian isoforms MT-1 and -2 are commonly isolated with seven 2ϩ Data deposition: The atomic coordinates for Zn4SmtA have been deposited in the Protein Zn ions bound exclusively to the thiolate groups of cysteine Data Bank, www.rcsb.org (PDB ID code 1JJD). residues in two clusters (8). In view of the cellular importance of ‡To whom reprint requests should be addressed. E-mail: [email protected] or zinc, there is considerable interest in establishing the conditions in [email protected]. which, and locations where, MT acquires or releases zinc (5, 9–13). The publication costs of this article were defrayed in part by page charge payment. This SmtA contains a smaller proportion of Cys than mammalian MT article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. (16% vs. 33% of residues), and, unlike mammalian MTs, contains §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.171120098 PNAS ͉ August 14, 2001 ͉ vol. 98 ͉ no. 17 ͉ 9593–9598 Downloaded by guest on September 30, 2021 111 ambient temperature with various mol equivalents of CdCl2 Table 1. NMR and structure statistics for Zn4SmtA 111 [prepared by dissolution of CdO (95.29%; Oak Ridge National Restraints for structure calculations (residues 5–56) Laboratory, TN) in 1 M HCl]. Excess metal was removed on a Total restraints 380 Sephadex G-25 column (prepacked Amersham Pharmacia PD-10) Total NOE restraints 291 ⅐ by elution with 50 mM Tris HCl buffer (50 mM NaCl, pH 7.0). Intraresidue 41 111 Typically, the Cd NMR spectrum was recorded ca. 30 min. after Sequential 79 2ϩ the addition of Cd . The incubation time had little effect on the Medium range 49 NMR spectra. Long range 122 Dihedral angles (␾)37 Metal Determinations. Samples of SmtA were diluted to 5 ml with Zinc distance restraints 52 50 mM Tris⅐HCl buffer and 50 mM NaCl. A Thermo Jarrell Ash IRIS inductively coupled plasma–atomic emission spectrometry Structure statistics (ICP-AES) instrument was calibrated by using five sulfur, zinc, or Number of starting structures 500 cadmium standard solutions in the same buffer, prepared from Number of final structures 20 1,000 ppm standards (Fisher Scientific), and the metal ion and Average of DIANA target function 0.67 Ϯ 0.13 sulfur contents were determined simultaneously, allowing the direct Number of violations Ͼ 0.25 Å none determination of the protein:metal ratio. rmsd to the average structure (residues 5–56), Å Backbone 0.90 Ϯ 0.11 Mass Spectrometry. Samples were prepared by buffer exchange into All heavy atoms 1.48 Ϯ 0.14 50 mM NH4Ac (Fisher Scientific) by using Amicon YM-3 centrif- ugation filters. Positive ion electrospray ionization (ESI)-MS was performed on a Micromass Platform II instrument on samples data points, using spectral widths of 8, 8, and 2.3 kHz, respectively. ␮ Ϫ1 diluted to 40 pmol l in 10% methanol. Samples at pH 2, 5, 7, and The data were transformed into 1 k ϫ 512 ϫ 64 data points. 10 were studied. MASS-LYNX (Version 2.3) software was used for One-dimensional 111Cd-{1H} NMR spectra [106.04 MHz, deconvolution of the spectra. Bruker (Ettlingen, Germany) DMX500,4kcomplex points] were acquired on a BBO (direct observe) probe head with 64 k transients Liquid Chromatography. The homogeneity of the protein prepara- (acquisition time 0.06 s, recycle delay 0.34 s). Longer acquisition tions was determined on a Hewlett Packard 1100 Series LC System, ϫ times or delays did not alter the spectra. Metal-ion-to-ligand employing a C18 reverse-phase column (250 4.6 mm, Lichrosorb, connectivities were determined by 2D [1H,111Cd] HSQC and 2D 5 ␮m diameter (BAS Technical, Congleton, UK); detection at 220 1 111 ␮ ␮ ⅐ [ H, Cd] HSQC-TOCSY NMR experiments: 256 transients were nm).
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