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1 Departments of Biochemistry and Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
2 Antimicrobial Research Centre and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
Reprint requests to: Albert M. Berghuis, Departments of Biochemistry and Microbiology and Immunology, McGill University, 3775 University St., Room 613, Montreal, Quebec H3A 2B4, Canada; e-mail: albert.berghuis{at}mcgill.ca; fax: (514) 398-7052.
(RECEIVED October 1, 2002; FINAL REVISION November 18, 2002; ACCEPTED November 18, 2002)
Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.0233503.
3 Present address: Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X5, Canada. 
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Keywords: Aminoglycoside acetyltransferase; antibiotic resistance; X-ray crystallography; N-acetyltransferase; dimerization
Abbreviations: AAC, aminoglycoside acetyltransferase • AAC(2')-Ic, aminoglycoside 2'-acetyltransferase type Ic • AAC(3)-Ia, aminoglycoside 3-acetyltransferase type Ia • AAC(6')-Ii, aminoglycoside 6'-acetyltransferase type Ii • AANAT, serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase) • AcCoA, acetyl coenzyme A • CoA, coenzyme A • GNAT, GCN5-related N-acetyltransferase • hPCAF, human histone acetyltransferase domain of P300/CBP associating factor • yGCN5, yeast GCN5 transcriptional activator • tGCN5, Tetramymena thermophila • GCN5, histone acetyltransferase domain • yHPA2, yeast histone acetyltransferase HPA2 • yHAT1, yeast histone acetyltransferase HAT1 • cNMT, Candida albicans N-myristoyl transferase • yNMT, yeast N-myristoyl transferase • GNA1, Saccharomyces cerevisiae GCN5-related N-acetyltransferase • RMSD, root-mean-square deviation
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Introduction |
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The resistance mechanisms bacteria use to avoid the effects of antibiotics are diverse, and range from active efflux, to drug–target alteration and enzymatic modification of drugs (Walsh 2000). For the class of antibiotics known as aminoglycosides, typified by gentamicin and kanamycin, the predominant mechanism of resistance is chemical modification of the drug, catalyzed by aminoglycoside-modifying enzymes (Shaw et al. 1993; Wright 1999; Burk and Berghuis 2002). Of these, N-acetyltransferases (AACs) are the most frequently found in clinical isolates (Miller et al. 1997).
AAC enzymes confer resistance by catalyzing the acetyl coenzyme A (AcCoA)-dependent acetylation of aminoglycoside antibiotics, reducing the affinity of these drugs for their bacterial target, the 16S ribosomal RNA, and impairing their ability to interfere with protein translation (Dickie et al. 1978). Despite the clinical relevance of AAC enzymes, structural studies have thus far been limited. Until recently, these studies consisted of structure determinations of AAC(3)-Ia in complex with coenzyme A (CoA) and AAC(6')-Ii with bound acetyl CoA (AcCoA) (Wolf et al. 1998; Wybenga-Groot et al. 1999). The structures of AAC(2')-Ic and its complexes with cofactor and substrates have now also been determined (Vetting et al. 2002). A comparison of the crystal structures of AAC(3)-Ia and AAC(6')-Ii revealed that despite limited sequence homology (<15%) the fold is remarkably similar. A similar conserved structural motif is also observed in the AAC(2')-Ic structure. A second common feature of these enzymes is their oligomeric state. The AAC(3)-Ia crystal structure strongly suggested that under physiologic conditions this enzyme is a dimer, based on the extensive interactions observed between the two noncrystallographically related molecules in the crystal form (Wolf et al. 1998). The AAC(2')-Ic is also known to be dimeric (Vetting et al. 2002). For AAC(6')-Ii, gel-filtration experiments (Wright and Ladak 1997) and dynamic light scattering studies (data not shown) similarly suggested that this enzyme is a dimer. Unfortunately, the crystal structure did not provide unequivocal data for the arrangement of this dimer due to their being only one molecule per asymmetric unit, compounded by an extremely high degree of crystal lattice symmetry (space group I4132). However, based on the structural differences between AAC(6')-Ii and AAC(3)-Ia, a dimer arrangement as observed for AAC(3)-Ia could be ruled out.
The similarity in fold observed between AAC(6')-Ii, AAC(3)-Ia, and AAC(2')-Ic is not limited to the class of AAC enzymes. In 1997, prior to any structural studies, Neuwald and Landsman predicted a common folding motif among a large group of diverse N-acetyltransferases, based on multiple sequence alignments. They named this group the GCN5-related N-acetyltransferase (GNAT) superfamily, as it is typified by the GCN5-related histone acetyltransferase (Neuwald and Landsman 1997). This prediction of a common folding motif has since been proven correct by over 10 crystallographic and NMR studies (Table 1
). Combined, these structural studies show that the common folding motif consists of 
90 residues, and that none of these residues are conserved across all family members (Neuwald and Landsman 1997). This finding has implications for the reaction mechanism employed by GNAT superfamily members (Wybenga-Groot et al. 1999). A number of the GNAT superfamily members that have been structurally characterized have been found to be multimeric, a phenomenon that has yet to be explored.
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Comparison of overall fold for CoA versus AcCoA bound forms of AAC(6')-Ii
The AAC(6')-Ii•CoA crystal form yields four crystallographically distinct enzyme molecules. The structures of these protomers were superimposed on each other, and on the AAC(6')-Ii•AcCoA structure (PDB: 1B87). The results of this analysis are depicted graphically in Figure 1. In most areas, the magnitude of the positional deviation observed between the AAC(6)-Ii•coA protomers and the AAC(6')-Ii•AcCoA structure is comparable to that observed among the main chain atoms of the four AAC(6')-Ii•CoA protomers. There are, however, three regions of the AAC(6')-Ii structure that appear to exhibit significant differences in atomic positioning between the CoA and AcCoA complexes: residues 53–56, residues 65–72, and residues 160–168.
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The conclusion to be drawn from the above observations is that the backbone conformation of the AAC(6')-Ii•CoA and AAC(6')-Ii•AcCoA structures is essentially identical and no gross conformational differences in the structure of AAC(6')-Ii can be attributed to the nature of the bound cofactor.
AAC(6')-Ii•CoA active site
As a first step, the four AAC(6')-Ii protomers in the crystallographic asymmetric unit were superimposed and examined. This procedure confirmed that the active sites are similar in structure in all four molecules. Figure 2 shows a stereo ball-and-stick representation of the superimposed coordinates of one of the CoA and AcCoA cofactors. As can be seen from the figure, the atoms of the acetyl CoA molecule superimpose well (1.2 Å RMSD) with the atoms of unacetylated CoA. Furthermore, the interactions between the adenosine-3'-phosphate moiety of coenzyme A and the enzyme are also largely conserved in both structures. Of the nine hydrogen bond interactions tethering the cofactor in the AAC(6')-Ii•AcCoA active site, seven are retained in the structure of the CoA bound form. The first of the additional interactions found in the AcCoA structure links the side chain hydroxyl group of Tyr147 and the sulfur atom of AcCoA, while the second links the carbonyl oxygen of Leu76 to an amino group of AcCoA. Neither of these hydrogen bonds is observed in the AAC(6')-Ii•CoA structure, and the resulting flexibility in the cofactor is reflected both in the increased positional deviations of these atoms between the superimposed AcCoA complex and the four protomers of AAC(6')-Ii•CoA, as well as in positional deviations in the four AAC(6')-Ii•CoA. The flexibility is also reflected in the poor electron density for the terminal half of the pantothenic acid and ß-mercaptoethylamine sections of the CoA molecule in all four AAC(6')-Ii•CoA protomers.
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The AAC(6')-Ii dimer interface is approximately 3000 Å2 in size (1500 Å2 per protomer), consistent with known dimeric species (Janin 1995). It can be considered as being composed of three regions. First, the edges of the central ß-sheets of the C-terminal lobes of AAC(6')-Ii protomers (ß5–ß6–ß7) associate with each other (Fig. 3). The two ß-sheets are linked by two main-chain hydrogen bonds between residues Val155 and Val157 of ß6 to residues Val157 and Val155, respectively, in the opposing protomer. The second component of the dimer interface consists of interactions between two loops from the C-terminal lobe of one protomer (ß5
4 and ß6ß7) with the C-terminal tail and an N-terminal loop (ß3ß4) of the other protomer (Fig. 3A, top left and bottom right of interfacial region). The third and final component of the AAC(6')-Ii dimer interface involves interactions between the 4 helices of the two protomers. Visible at the top of Figure 3B, they are oriented such that their helical axes are roughly parallel to each other. The interaction between the helices is hydrophobic in nature, occurring between the aromatic side chains of Phe130 in the two protomers (Fig. 3C).
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Comparison of AAC(6')-Ii dimer with other oligomeric GNAT enzymes
Despite limited sequence conservation, GNAT superfamily members share a common folding motif, consisting most generally of a four-stranded mixed ß-sheet and two -helices—one on each side of the ß-sheet. Figure 4 illustrates the members of the GNAT family whose three-dimensional atomic structures have been determined and have been observed to form multimeric complexes. As can be seen in Figure 4A, the structurally conserved segments of the motif are remarkably similar in the five enzymes, differing principally in their C-terminal regions and in the size of the loops between their secondary structural elements. The structures of the GCN5-related N-acetyltransferases have recently been reviewed (Dyda et al. 2000).
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are of the members of the GNAT superfamily that are known to be multimeric. The question that has thus far not been addressed is whether the multimeric GNAT members are assembled in similar ways, and what features distinguish this subset from the monomeric members of the GNAT superfamily? Figure 4B shows cartoon representations of the five multimeric members of the GNAT enzyme superfamily. Four of the enzymes, AAC(6')-Ii, AAC(3)-Ia, GNA1, and AAC(2')-Ic, form dimeric complexes, while a fifth, yHPA2, forms a dimer in solution and a tetramer upon binding AcCoA (Angus-Hill et al. 1999). As the figure shows, the five multimeric GNAT superfamily members have a number of structural similarities, but also some interesting differences as well. The AAC(6')-Ii and AAC(2')-Ic protomers are distinguished from the others by their large C-terminal lobes, a feature lacking in the protomers of AAC(3)-Ia, yHPA2, and GNA1. In the AAC(6')-Ii dimer, the protomers associate mainly through interactions involving the extended C-terminus of the protein as described previously (see Fig. 4B). The main interactions linking the AAC(6')-Ii dimer assembly are shown schematically in Figure 5A.
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). Although the C-terminus of this protein is less extensive than that of AAC(6')-Ii (lacking an additional strand in the C-terminal ß sheet), there are similar interactions in both dimer species. The same ß3ß4 turn that is involved in interdimer interactions in AAC(6')-Ii is also implicated here (referred to as S3S4 in the original article). However, in the AAC(3)-Ia dimer, the turn interacts with an interhelical loop (23) on the back of the hand of the GNAT motif, rather than with a loop from the C-terminal lobe. As with AAC(6')-Ii, the AAC(3)-Ia dimer interface also involves interactions between the residues of the C-terminal section of the protein. In AAC(3)-Ia, these interactions consist of hydrogen bonds between the ß5ß6 loop region and the ß6 ß-strand, as well as interactions between the two ß6 strands themselves. The AAC(3)-Ia dimer is therefore similar to that of AAC(6')-Ii, in that both feature hydrogen bonds between ß-strands as core interdimer interactions. However, they differ in that the AAC(6')-Ii protomers incorporate an additional ß-strand (ß7) as part of their expanded C-terminus, and as a result, the orientation of the interacting strands is different from that of AAC(3)-Ia. A schematic representation of the central AAC(3)-Ia dimer interactions is shown in Figure 5B (also Fig. 6).
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) is similar in construction to that of AAC(3)-Ia. Although slightly more extensive than that observed in AAC(3)-Ia, the C-terminal lobe of the yHPA2 protomer is not so large as to require a change in the mode of dimer association (as seen with AAC(6')-Ii). The interdimer interactions are similar to those observed in AAC(3)-Ia. One notable difference is that in the yHPA2 dimer, one of the ß-strands of the C-terminal lobe of a protomer interdigitates with the strands of the other protomer. This difference in dimer interactions can be appreciated by referring to Figure 5. With minor differences, GNA1 has interdimer interactions similar to yHPA2. N-myristoyl transferase (NMT) is unique in the GNAT superfamily in that it exhibits twofold internal symmetry and possesses two copies of the conserved structural motif. This enzyme appears to have evolved following a gene duplication event (Weston et al. 1998). Interestingly, once again the orientation of the GNAT motif is similar to that observed in the AAC(3)-Ia, yHPA2, and GNA1 dimers.
The most recently determined multimeric GNAT superfamily member is AAC(2')-Ic. At first glance, this dimer structure (Vetting et al. 2002) is reminiscent of the AAC(6')-Ii dimer. However, although both have extensive C-terminal lobes, the relative arrangement of the GNAT motifs in the two dimers is very different. In the AAC(2')-Ic structure, one of the conserved GNAT structural motifs is rotated with respect to its AAC(6')-Ii counterpart (Fig. 6).
Figure 5 shows that there are underlying similarities in interdimer interactions between four of the five dimers. In these dimers, main-chain to main-chain hydrogen bonds between adjacent ß-strands form a core set of interactions that assist in the maintenance of the dimer structure. However, there appear to be at least three variations on this theme. Perhaps the simplest arrangement is that of AAC(3)-Ia, in which the two C-terminal strands of the protomers are grouped together. In AAC(6')-Ii, due to the presence of an additional strand in the C-terminal lobe of the protein, the direction of the interacting strands is opposite to that of AAC(3)-Ia. Finally, in the case of yHPA2 and GNA1, the interactions are again between adjacent ß-strands, but due to the swapping of strands between the two protomers, the strands are from different molecules.
Given an understanding of the predominant modes of dimer formation observed in GNAT enzymes, it may be instructive to examine the structural basis for the absence of oligomerization in the monomeric members of the GNAT superfamily. One example of a monomeric GNAT superfamily member is serotonin N-acetyltransferase (AANAT). In AANAT, the ß3ß4 and 12 regions of the protein consist of large loop structures. These large loops would appear to preclude the association of two AANAT monomers in a manner similar to that observed for most of the multimeric GNAT enzymes. Similarly, the structure of Tetrahymena GCN5 reveals a loop structure in the C-terminal lobe that apparently prevents dimer formation.
The oligomerization state of members of the GNAT superfamily is, however, not governed simply by the extent of loops between elements of secondary structure. The structure of an AAC(2')-Ic monomer, with its significant additions to the core GNAT structural motif, suggests that a dimeric structure would not be expected for this enzyme. Despite this, the AAC(2')-Ic enzyme has evolved into a dimeric form—one that is, however, significantly different in structure from those of the other oligomeric superfamily members.
Evolution of GNAT oligomers
The fact that there are oligomeric GNAT superfamily enzymes raises the question of why these multimers exist. The driving force behind oligomerization is genetics, and thus it must ultimately confer a biologic advantage (D’Alessio 1999). A number of advantages of multimeric proteins can be imagined, such as the presence of a multiplicity of interacting binding sites for substrates (Goldberg et al. 1975; D’Alessio 1999). However, for oligomers in the GNAT superfamily, such as AAC(6')-Ii, AAC(3)-Ia, and AAC(2')-Ic, the biologic advantage conferred by their multimeric structure is not clear.
The mechanism by which oligomeric proteins evolve has been an important question for some time. Oligomerization was generally thought to occur as a consequence of random mutations on the surface of monomeric proteins. Because the solvent-accessible surface area of dimer interfaces ranges from approximately 700 to 5000 Å2 (Janin 1995), such a mechanism would require multiple simultaneous mutations. Because this seems unlikely, the mechanism of dimer evolution has remained enigmatic. More recently, the idea of three-dimensional domain swapping has been proposed as an alternative mechanism for the evolution of oligomeric proteins (Bennett et al. 1995). In the GNAT superfamily, we have a diverse collection of monomeric species, different dimers, as well as internal dimers. To our knowledge, this superfamily is unique in this regard, and it represents an interesting model system for the study of dimer evolution.
A number of monomeric GNAT superfamily enzymes exist that are structurally similar to the components of the oligomeric superfamily members. This suggests that the components of the multimeric enzymes could form stable monomers. One can imagine an ancestral monomeric version of a GNAT oligomer that undergoes mutation of surface residues that predisposes it to adhering to another. This is one possible explanation for the evolution of the AAC(3)-Ia, AAC(2')-Ic, and AAC(6')-Ii dimers. The differences in the variable regions of AAC(3)-Ia, AAC(2')-Ic, and AAC(6')-Ii may represent an accumulation of mutations that have stabilized the assembly in different ways.
In the case of yHPA2 and GNA1, the evolutionary pathway appears to be different, having included the phenomenon of domain swapping. In these dimers, mutations have led to the swapping of an element of secondary structure between the two subunits. The present active sites are composed of residues from both protomers, suggesting that the catalytic machinery of the active site evolved after dimer formation. Intriguingly, despite the apparently different evolutionary paths, the orientation of the GNAT structural motifs are similar in the AAC(3)-Ia, yHPA2, and GNA1 dimers.
The observation that the different oligomeric members of the GNAT superfamily form their assemblages in different ways raises the question of their evolutionary relationship. A phylogenetic analysis of the structurally characterized members of the superfamily, both monomeric and oligomeric, could shed further light on the possible route of oligomer evolution (Fig. 7). One of the first observations to be made is that the oligomeric and monomeric superfamily members are not grouped together. Second, the three types of dimers observed in the GNAT superfamily are also not grouped together. This is somewhat surprising, because one might expect similar dimer arrangements to be adjacent on the phylogenetic tree. Instead of being grouped together, swapped GNAT dimers are present in three of the branches of the tree. One possible interpretation is that the swapped dimers represent the ancestral dimeric form, and that the other dimer arrangements evolved from them. However, there are several other possible interpretations of the phylogenetic data.
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Diffraction data were collected from a single crystal at the X8C beam line of the National Synchrotron Light Source, Brookhaven National Laboratories in Upton, NY. The wavelength of the incident X-ray beam was 1.0722 Å, and the resultant diffraction images were recorded using the ADSC Quantum 4 CCD area detector. During data collection, the crystal was maintained at cryogenic temperatures so as to reduce radiation damage. Diffraction data were collected in two passes—a low resolution pass and a high resolution pass. For the low resolution pass, the crystal to detector distance was set to 210 mm and the exposure time for the 1.0° oscillation images was kept relatively short, resulting in a 2.5 Å resolution data set with few overloads. For the high resolution pass, the crystal to detector distance was set to 150 mm and the exposure time was doubled, resulting in a 1.8 Å resolution data set containing numerous overloads at low resolution, but acceptable signal to noise ratios for high resolution reflections.
Data processing of the diffraction data was performed with the HKL suite of programs (Otwinowski and Minor 1997). Data originating from the two passes were merged during the scaling of individual frames in SCALEPACK. Statistics related to data quality are provided in Table 2.
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. The final coordinates and structure factors have been deposited with the Protein Data Bank (accession number 1N71).
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Acknowledgments |
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The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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References |
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M. W. Vetting, L. P. S. de Carvalho, S. L. Roderick, and J. S. Blanchard A Novel Dimeric Structure of the RimL N{alpha}-acetyltransferase from Salmonella typhimurium J. Biol. Chem., June 10, 2005; 280(23): 22108 - 22114. [Abstract] [Full Text] [PDF]
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M. W. Vetting, S. L. Roderick, M. Yu, and J. S. Blanchard Crystal structure of mycothiol synthase (Rv0819) from Mycobacterium tuberculosis shows structural homology to the GNAT family of N-acetyltransferases Protein Sci., September 1, 2003; 12(9): 1954 - 1959. [Abstract] [Full Text] [PDF]
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