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Human Molecular Genetics Advance Access originally published online on September 20, 2005
Human Molecular Genetics 2005 14(21):3203-3217; doi:10.1093/hmg/ddi351
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship

M. Sardiello1, I. Annunziata1, G. Roma1 and A. Ballabio1,2,*

1Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy and 2Medical Genetics, Department of Pediatrics, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy

* To whom correspondence should be addressed. Tel: +39 816132207; Fax: +39 815790919; Email: ballabio{at}tigem.it

Received June 30, 2005; Accepted September 14, 2005

DDBJ/EMBL/GenBank accession nos{dagger}


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 ECR Analysis
 REFERENCES
 
Sulfatases catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates. Several human inherited diseases are caused by the deficiency of individual sulfatases, while in patients with multiple sulfatase deficiency mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene cause a defect in the post-translational modification of a cysteine residue into C{alpha}-formylglycine (FGly) at the active site of all sulfatases. This unique modification mechanism, which is required for catalytic activity, has been highly conserved during evolution. Here, we used a genomic approach to investigate the relationship between sulfatases and their modifying factors in humans and several model systems. First, we determined the complete catalog of human sulfatases, which comprises 17 members (versus 14 in rodents) including four novel ones (ARSH, ARSI, ARSJ and ARSK). Secondly, we showed that the active site, which is the target of the post-translational modification, is the most evolutionarily constrained region of sulfatases and shows intraspecies sequence convergence. Exhaustive sequence analyses of available proteomes indicate that sulfatases are the only likely targets of their modifying factors. Thirdly, we showed that sulfatases and ectonucleotide pyrophosphatases share significant homology at their active sites, suggesting a common evolutionary origin as well as similar catalytic mechanisms. Most importantly, gene association studies performed on prokaryotes suggested the presence of at least two additional mechanisms of cysteine-to-FGly conversion, which do not require SUMF1. These results may have important implications in the study of diseases caused by sulfatase deficiencies and in the development of therapeutic strategies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 ECR Analysis
 REFERENCES
 
Sulfatases represent a large protein family that is involved in heterogeneous processes, ranging from the degradation of macromolecules to hormone biosynthesis and the modulation of developmental cell signaling (1Go–3Go). Sulfatases hydrolyze sulfate esters from different sulfated substrates such as steroids, carbohydrates, proteoglycans and glycolipids. Comparison of the crystal structures of one bacterial and three human sulfatases (4Go–7Go) showed that they have a highly similar three-dimensional structure in addition to a superimposable core region, which constitute the catalytic site of the enzymes (2Go,4Go). This has a well-conserved peptide substructure including a divalent metal ion located within a pocket in which substrates are bound. Several residues that protrude toward the pocket appear to have identical functions in the catalytic mechanisms that generate and resolve the enzyme-sulfate ester intermediate. Critical residues involved in these processes are conserved in most sulfatases (2Go,4Go), therefore supporting their common role to form similar active sites regardless of the different substrates that are hydrolyzed. All of investigated sulfatases contain, at their catalytic site, a C{alpha}-formylglycine (FGly) residue that is essential for enzyme activity (8Go,9Go). FGly formation occurs post-translationally by the oxidation of a cysteine residue that is conserved in all eukaryotic sulfatases as well as in most prokaryotic sulfatases (8Go,10Go). However, some bacterial species produce FGly by the oxidation of a serine instead of a cysteine (9Go,11Go), which is located at the same position of the active site. This led to the classification of prokaryotic sulfatases as either ‘Cys-type’ or ‘Ser-type’ (12Go,13Go).

Sulfatases are believed to descend from a common ancestral gene (1Go,14Go). Thirteen human sulfatase genes have been reported to date (2Go,15Go,16Go). They encode enzymes that, after targeting to the secretory pathway and extensive glycosylation, are transported to their final subcellular compartment—lysosome, Golgi complex or endoplasmic reticulum (ER)—or extruded to the extracellular matrix (2Go). Deficiencies of single sulfatase activities are responsible for several human inherited diseases including five different types of mucopolysaccharidoses (17Go), metachromatic leukodystrophy (18Go), X-linked ichthyosis (19Go) and chondrodysplasia punctata (CDPX) (20Go). In multiple sulfatase deficiency (MSD), a rare inherited human disease in which all sulfatase activities are simultaneously defective, the post-translational conversion of cysteine to FGly is impaired (8Go). The gene responsible for MSD was recently identified (21Go,22Go). This gene, named Sulfatase Modifying Factor 1 (SUMF1), is a member of a gene family that has been highly conserved during evolution, from bacteria to humans (23Go): SUMF1 encodes the formylglycine-generating enzyme, which is responsible for the cysteine to FGly conversion. This protein is not homologous to AtsB, the previously identified bacterial protein involved in the post-translational modification of Ser-type sulfatases (9Go,12Go). Therefore, the current paradigm of FGly formation describes two separate, independent mechanisms acting on either Cys-type sulfatases or Ser-type sulfatases and involving either SUMF1 or AtsB modifying factors, respectively.

In eukaryotes, post-translational modification of the cysteine residue into catalytically active FGly occurs in the ER at a stage when the polypeptide is not yet folded into its native structure (10Go,24Go). A small sulfatase peptide segment, containing the cysteine to be modified and some highly conserved surrounding residues, is both necessary and sufficient to direct FGly formation (10Go,25Go). This peptide segment, henceforth referred to as ‘sulfatase signature’, spans over a 12-mer linear sequence starting from the cysteine to be modified. A core motif C/S-X-P-X-R is conserved across the signatures of the entire enzyme class (10Go,25Go) including eukaryotic sulfatases and both bacterial Cys-type and Ser-type sulfatases. Two in vitro mutagenesis studies (25Go,26Go) established that the residues contained in this core motif constitute the information necessary for the modification machinery to target the cysteine residue to be modified into FGly. These residues have also been described as critical structural elements to the proper configuration of the active site (26Go).

Some fundamental questions that have remained unanswered so far are the following: What proteins comprise the full set of mammalian sulfatases? Are there any additional cellular targets of sulfatase modifying factors other than sulfatases? Are there mechanisms, not requiring SUMF1, able to perform the post-translational modification of Cys-type sulfatases? To answer these questions, we used a genomic approach for the analysis of sulfatases and sulfatase modifying factors and their relationship in nearly all the fully sequenced eu- and prokaryotic organisms.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 ECR Analysis
 REFERENCES
 
Defining the complete catalog of mammalian sulfatases
We performed search analyses for sulfatase genes across the human, mouse, rat and dog genomes using the TBLASTN and BLAT algorithms at the National Center for Biotechnology Information (NCBI) and at the University of California at Santa Cruz (UCSC) genome browsers, respectively. The search was performed using the sequences of known mammalian sulfatases as queries. The retrieved genomic sequences were compared to the available cDNA/EST sequences to infer the gene structures. For genes that lacked a transcript counterpart in public databases, we performed a careful manual comparison of the genomic sequences with the putative closest ortholog or paralog (see Materials and Methods) using pairwise TBLASTN and TBLASTX, looking for splicing donor and acceptor signals to define the gene architectures. We also performed a PSI-BLAST search against mammalian proteins using as a probe the string C[ACST]PSR[ASV][AQS][LFIM][LIM]TG, representative of the catalytic sites of previously described human sulfatases.

The combined utilization of these methods led us finally to annotate a total of 17 human, 17 dog and 14 rodent sulfatase genes (Table 1) (GenBank accession nos AY875937–AY875940; BN000735–BN000767). Four human sulfatase genes which had not been reported previously resulted from our analyses. We named these genes Arylsulfatase H (ARSH), Arylsulfatase I (ARSI), Arylsulfatase J (ARSJ) and Arylsulfatase K (ARSK). ARSH is located at Xp22.3 within a sulfatase gene cluster that includes ARSD, ARSE and ARSF and shares with these genes the same exon/intron organization as well as a high degree of identity of the encoded proteins (see Online Supporting Data at http://sulfabase.tigem.it). ARSI and ARSJ encode similar proteins (57% amino acid identity) and span only two exons, different from all the other human sulfatase genes that span 8–20 exons. Peptide comparison showed that ARSI and ARSJ are closely related to ARSB (45–48% amino acid identity), whereas they showed a lower degree of similarity to the other human sulfatases. These data suggest that ARSI and ARSJ should be regarded as ARSB paralogs, which possibly originated from a single retrotranscription event of the ARSB mRNA, followed by intron insertion and locus duplication. ARSK encodes a protein that is 18–22% identical and 32–38% similar to human sulfatases of comparable size and, different from ARSH, ARSI and ARSJ, does not show paralogous relationships with any previously described sulfatase.


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  		Table 1. The complete set of sulfatases in humans (Hs), dog (Cf), mouse (Mm) and rat (Rn)
 
Comparative analyses showed that all mammals analyzed share the same complement of sulfatases, with the exception of ARSD, ARSE, ARSF and ARSH, which are organized in X-linked clusters in the human and dog genomes but have only one homologous gene in mouse and rat (Arse) at chromosomes X and 2, respectively. Another exception is the lack of a rat SGSH ortholog; however, a microsynteny analysis (i.e. an investigation of local gene repertoire, order and orientation) among rat, human, dog and mouse suggested that a sequence gap located at rat 10q32.3 could account for this discrepancy (see Online Supporting Data at http://sulfabase.tigem.it). It was previously suggested that the human sulfatase cluster located at Xp22.3 originated by successive steps of recent duplication events that occurred in an ancestral pseudoautosomal region (14Go). Comparison of the percentages of amino acid identity/similarity of human ARSD, ARSE, ARSF and ARSH (Fig. 1A) strongly suggests that all duplication events that led to the cluster formation occurred in a relatively small time lag during evolution. This comes from the observation that the percentages of all pairwise comparisons are included in small ranges (60–65% amino acid identity, 73–78% amino acid similarity), indicating that these genes started to diverge approximately in the same evolutionary period and therefore suggesting near-concomitance of gene duplication at the origin of the gene cluster. Among the four clustered sulfatases, ARSE has the highest amino acid identity to the only mouse and rat counterpart (see Online Supporting Data at http://sulfabase.tigem.it). We used the statistic KS (the mean number of synonymous substitutions per synonymous site within the coding regions) to provide an estimate of the possible order of duplications from which the gene cluster originated (description in Fig. 1B). The results support the hypothesis that human ARSE was the cluster's founder and, together with the higher similarities between the encoded peptides, that murine Arse and human ARSE could be functional orthologs. This finding is of significance because defects in ARSE are the cause of X-linked recessive CDPX (20Go), a congenital disease characterized by abnormalities in cartilage and bone development with variable degrees of severity and so far no murine counterpart of ARSE could be identified (14Go), which has hampered the possibility of developing a murine CDPX model.



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  		Figure 1. Evolutionary relationships among human sulfatases ARSD, ARSE, ARSF and ARSH. Both pairwise peptide sequence comparison and synonymous nucleotide substitution relative rates (A) were used to infer the most likely order of duplication that generated the gene cluster beginning from the ARSE ancestor (B). In the proposed model, sequential steps of duplication event (1Go–3Go) generated the ARSD, ARSH and ARSF genes, respectively. A successive single inversion event (4Go) rearranged the locus to its current shape. Identities/similarities between amino acid sequences are shown in blue; synonymous nucleotide substitution relative rates (KS) are shown in red. Genes (green head arrows) are oriented according to the direction of transcription.

 
In addition to the sulfatase genes listed in Table 1 and some Y-linked sulfatase pseudogenes previously described (14Go), no other genes similar to sulfatases resulted from our analyses in any investigated mammalian genome. Overall, the set of mammalian sulfatases which we present here shows a strong phylogenetic coherence, suggesting that it is complete and can be used as a basic model for expected sulfatase genes in any primate, carnivore or rodent species. A search of the invertebrate Drosophila melanogaster and Caenorhabditis elegans genomes and proteomes showed that these species have different complements of sulfatases with respect to mammals. The fruitfly has a total of eight sulfatases, which includes putative orthologs of mammalian IDS, GALNS and SGSH and homologs of SULF1/2 and ARSB/I/J. C. elegans has only three sulfatases, two of which can be regarded as homologous to SULF1/2 and ARSB/I/J, respectively. The third worm sulfatase has a more uncertain phylogenetic collocation. Sequence comparisons between homologous vertebrate and invertebrate sulfatases are publicly available at http://sulfabase.tigem.it.

Determination of the complete set of human sulfatases allowed us to perform a global analysis of their amino acid sequences. Human sulfatases have widely divergent segments because of the different substrates processed as well as their different compartmentalization at the subcellular level (see Introduction). However, it is believed that the general scheme of the enzymatic reaction performed by sulfatases is identical in all cases, which implies that all these enzymes share a common minimum number of substructures and residues participating in substrate stabilization and hydrolysis (2Go,3Go). As functionally important sites in a protein are subject to selective constraints, their evolutionary rates of change are significantly lower than the remaining sites of the protein. Therefore, identifying evolutionarily constrained regions (ECRs) can translate into inferring important functional regions across the protein length (27Go).

By analyzing the evolutionary profile of human sulfatases, we identified nine regions with strong conservation (ECRs A to I) (Fig. 2A). Remarkably, most identified ECRs contain the residues described as involved in the hydrolysis reaction of sulfatases (Table 2). Our analysis identified also three conserved regions (ECRs E, H and I) in protein segments of unknown function. In ARSA, ECR I overlaps with a protein loop located at the interface between the two homodimer-forming monomers (6Go), whereas ECRs E and H include conserved residues that, if mutated, prevent appropriate protein folding and subsequent localization, which suggests a structural role for these ECRs as previously described (28Go). An extensive search of the Human Gene Mutation Database (http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html) (29Go) and published literature revealed that seven out of 11 conserved amino acid residues of unknown function placed within reported ECRs have been found to be mutated in several human diseases (see Table 2 and references therein). Interestingly, some of these sites are placed within the cavity that hosts the active site of the enzymes (Table 2), as shown by the three-dimensional structures of human ARSA, ARSB and ARSC. These residues are possible candidates for participation in the hydrolysis reaction and will, therefore, be excellent targets for explorative biochemical and structural analysis.



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  		Figure 2. Amino acid analysis of human sulfatases. (A) A plot of local evolutionary rates across human sulfatases is shown, along with the peptide sequence alignment used in the analysis. All positions containing a sequence gap in >35% of sulfatases were removed (Materials and Methods). The values plotted along the y-axis are derived from the average number of amino acid substitutions per site for residues at the corresponding x-axis position. The red lines at the bottom mark the nine highest scoring ECRs detected (ECRs A to I from N- to C-terminal). Red asterisks indicate amino acids with a known function in the hydrolysis reaction. Green asterisks indicate novel candidates for playing a direct role in the hydrolysis reaction, here identified as amino acids included in ECRs and showing >90% similarity across all sulfatases (glycines and prolines are excluded from the analysis). An editable version of the alignment is available at http://sulfabase.tigem.it. (B) An alignment between the ARSC trans-membrane domain and its homologous sequences from ARSD, ARSE, ARSF and ARSH is shown, along with the known (orange-shaded) (7Go) and putative (gray-shaded) trans-membrane amino acid segments. The figure shows that the candidate trans-membrane segments strictly correspond to their homologous counterpart from ARSC, despite a general low degree of amino acid similarity. The topology prediction of membrane proteins was performed using the TopPred software available at the Pasteur Institute web server (http://bioweb.pasteur.fr/seqanal/interfaces/toppred.html). Amino acids with >90% similarity are in red. Amino acids with >50% similarity are in blue.

 

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  		Table 2. Conserved residues within evolutionary conserved regions (ECRs) of human sulfatases
 
We also examined sulfatases for the presence of candidate membrane-spanning domains. The results showed that ARSD, ARSE, ARSF and ARSH (the paralogous sulfatases located at Xp22.3) have two putative membrane-spanning segments each, which correspond to the two trans-membrane domains of ARSC previously described (7Go) (Fig. 2B). This result was not unexpected, because ARSC and these four sulfatases share a general high degree of similarity and they are believed to have descended from a common ancestor gene before mammalian radiation (14Go). ARSD, ARSE, ARSF and ARSH are therefore novel candidate integral membrane proteins. Protein comparison also showed that these putative trans-membrane segments are exclusive of these five sulfatases. The examination of sulfatases from the other mammalian species gave identical results (data not shown).

Sulfatases and ectonucleotide pyrophosphatases show significant homology at their active sites
By means of comparative analyses, we identified the ectonucleotide pyrophosphatase (ENPP) protein family as the closest human protein group to sulfatases. ENPPs are enzymes involved in the cleavage of a variety of substrates, including phosphodiester or pyrophosphate bonds of nucleotides and nucleotide sugars (30Go). In silico genome searching and analysis of published literature showed that ENPPs have been evolutionarily conserved from bacteria to higher eukaryotes, with protein members in most species we examined (data not shown). We also identified members of a prokaryotic phosphonate monoester hydrolase (PMH) group as very similar to some bacterial sulfatases at the primary sequence level. PMHs have been reported to hydrolyze a variety of phosphonate esters and phosphodiesters (31Go). The analysis of available genome sequences, however, showed that PMH group is limited to a few bacterial species from the Proteobacteria phylum (see Online Supporting Data at http://sulfabase.tigem.it).

The amino acid comparison of the active sites of sulfatases, ENPPs and PMHs showed that all three groups of enzymes share conserved or similar residues at the same positions (Fig. 3A), suggesting a common evolutionary origin for these protein families as well for the reactions they catalyze. Interestingly, a common origin between sulfatases and phosphatases was previously suggested on the basis of structural observations (5Go,6Go). The catalytic site of ENPPs is a threonine residue, which occupies the same place at the active site as the FGly within sulfatases (Fig. 3A). Because of similarities between ENPPs and sulfatases, as well of the broad distribution of ENPPs in both prokaryotes and eukaryotes, it is likely that sulfatases evolved from ENPPs, after the appearance of the post-translational modification. PMHs show overall higher homology degrees to sulfatases than ENPPs (data not shown) and carry a cysteine residue at their active site in their predicted protein sequences (Fig. 3A), which makes them possible candidates outside the sulfatase class to be targeted by the FGly-generating system. Gene association studies aimed to investigate this possibility are described in a following section.



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  		Figure 3. Logo representation of the catalytic cores of sulfatases, phosphonate monoester hydrolases (PMHs) and ectonucleotide pyrophosphatases (ENPPs). The overall height of each column is proportional to the information content at that position, and within columns the conservation of each residue is visualized as the relative height of symbols representing amino acids. Position 1 indicates the residues directly involved in the enzymatic reaction. Position 1 of sulfatase cores indicates the amino acid (cysteine or serine) to be modified into FGly. (A) Comparison of the catalytic cores of sulfatases, PMHs and ENPPs shows that positions 3, 5, 10 and 11 contain the residues best conserved among the members of each enzyme family and among the three protein families. (B) A comparison of the FGly formation-directing signature of mammalian, fly and worm sulfatases. Human signatures were used as representatives of all mammals due to the strong sequence identity (>99%) presented by mammalian orthologous proteins at this site. Sulfatase signature logos show that only positions 3 (proline), 5 (arginine) and 11 (glycine), in addition to the cysteine to be modified, are completely conserved in all examined organisms. In addition, human and fly signatures show intraspecies sequence convergence at positions 4 (serine) and 8 (leucine), respectively.

 
Sulfatase signatures show intraspecies sequence convergence
Ranking ECRs by their local evolutionary rates can be predictive of functional importance (27Go). The FGly-containing signature is the most evolutionary constrained region of human sulfatases (Fig. 2A and Table 2), possibly due to its dual role as active site and target of the post-translational modification system. Other functionally important regions, as those containing residues involved in substrate binding and activation and metal coordination, also rank high when ordered by their evolutionary rates (Table 2). Conversely, examining the evolutionary profiles of orthologous proteins for each individual type of sulfatase from invertebrates to mammals revealed that the FGly-containing segment never ranks as the most evolutionary constrained region (Table 3) (all evolutionary profiles are reported as Online Supporting Data at http://sulfabase.tigem.it). In each sulfatase type, one or more regions are more conserved than the active site.


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  		Table 3. Ranking and relative rates of sulfatase signatures in different groups of sulfatases
 
An analysis of all Drosophila sulfatases revealed that, like in human sulfatases, the FGly-containing segment is the most evolutionary conserved region (Table 3 and the evolutionary profile at http://sulfabase.tigem.it). This sequence convergence shown by the active sites of both human and Drosophila sulfatases may be the result of the need of this protein segment to be recognized by the modification machinery in each species. Interestingly, the active site of sulfatases is less conserved and ranks only third among all detected worm ECRs (Table 3 and the evolutionary profile at http://sulfabase.tigem.it).

To evaluate the conservation of each position within the catalytic sites of mammalian, fly and worm sulfatases, henceforth indicated as ‘sulfatase signature’, we performed a logo (32Go,33Go) analysis of their amino acid sequences, focusing on positions from –2 to +12 with respect to the cysteine to be modified. The comparison was performed including only one gene for each group of paralogous sulfatases, to avoid a biasing effect due to identical residues within sulfatases arisen recently from a common ancestor. The results showed that all sulfatase signatures share only four invariant positions: the cysteine to be modified (henceforth indicated as position +1), a proline at position +3, an arginine at +5 and a glycine at +11 (Fig. 3B). Position +10 presents a strong bias for threonine, which is substituted by a serine in all mammalian ARSKs and in Drosophila pCG32191. Worm signatures show no further fully conserved residue and also show divergence at many positions (Fig. 3B). Conversely, mammalian and fly signatures are overall more conserved, and they present additional invariant residues at the positions +4 and +8, respectively (Fig. 3B).

Species-specific convergence observed at mammalian and fly sulfatase signatures suggests that these protein segments had evolved under specific evolutionary pressure to meet precise requirements of the modifying system that is present in each species. Specific invariant residues are therefore likely to play a role in the process of recognizing the cysteine to be targeted by the modification machinery, as previously suggested for human positions +3 to +5 by in vitro mutagenesis studies (25Go,26Go). It is likely that the convergence of the mammalian and fly sulfatase signatures, as well as their current sequences, is the result of co-evolution with their respective cognate modifying factors. Interestingly, an exhaustive search of the worm genome failed to find neither obvious nor distant SUMF1 homologs. This could explain the lower evolutionary constrains observed at the worm sulfatase signature in terms of a weaker evolutionary pressure under which the worm signature evolved. It remains unclear whether C. elegans has its own peculiar modifying machinery for cysteine-to-FGly conversion or even whether FGly formation actually occurs in worm.

Recognition sites for the FGly-generating system are specific for sulfatases
To identify potentially novel proteins undergoing the cysteine to FGly modification, we downloaded the complete human proteome set from the Ensembl genome browser (ftp://ftp.ensembl.org/pub/current_human/) and performed pattern search analyses using signature-like stretches as probes. A preliminary analysis performed with the complete mammalian invariant sequence CxPSRxxxx[T/S]G showed that this motif is present in no other proteins but in sulfatases. The analysis performed using as a probe the signature core CxPSR showed that this motif is present in 87 non-redundant human proteins (0.39% of the complete Ensembl human protein set). A control analysis performed with the motif CxxPSR, which shares with CxPSR both similar amino acid composition and order but is assumed to have no biological significance, yielded a comparable result (64 non-redundant proteins, corresponding to 0.29% of the complete human protein set). This suggested that a consistent proportion of the 87 CxPSR motifs we identified might be background noise.

We expected that CxPSR motifs directing FGly formation would be conserved among mammalian homologous proteins, as it occurs for sulfatases. Therefore, to distinguish potentially true CxPSR sites from background noise, we searched the mouse, rat and dog genomes using the 87 CxPSR-containing human protein sequences as probes. The genes we identified as putative orthologs were confirmed by either microsynteny analysis or best-reciprocal-hit analysis. A sequence analysis of their gene products showed that 38 out of 87 examined proteins retain the CxPSR motif in both dog and rodents. Then, we analyzed their sequences for the presence of a signal peptide for targeting to the ER—the subcellular compartment where conversion of cysteine into FGly occurs (10Go,24Go). The results showed that signal peptides are present in only 17 proteins, which correspond to the earlier-described sulfatases.

We chose D. melanogaster as a distant organism to perform a similar analysis. Examination of fly protein sequences (downloaded at ftp://ftp.ensembl.org/pub/current_fly/) showed that the fly signature motif CxP[SA]RxxLx[ST]G is exclusive to sulfatases, whereas the partial signature motif CxP[SA]RxxL is present also in four unrelated proteins. However, the analysis of their homologous sequences from Drosophila pseudoobscura and malaria mosquito Anopheles gambiae showed that this motif was not conserved in these fruitfly-related species. We then searched the D. melanogaster proteome for the presence of the signature core CxP[SA]R and found this motif in a total of 41 non-redundant proteins (0.30% of the complete fly protein set). Sequence comparison with their homologous sequences from D. pseudoobscura and malaria mosquito showed that only 14 out of the 41 examined proteins retain the core motif in these species. Finally, examination of these 14 proteins showed that only sulfatases are provided with a signal peptide for the ER.

These data clearly support the conclusion that the relationship between sulfatases and the FGly-generating system is exclusive in these species. Therefore, if SUMF1 is the only FGly-generating enzyme in higher eukaryotes, then sulfatases are the only likely proteins to carry this unique amino acid.

Sulfatase genes are clustered with their modifying factors in prokaryotic genomes
Functional coupling between genes can be inferred on the basis of the conservation of gene clusters among bacterial genomes (34Go,35Go). Preliminary data on gene association of bacterial sulfatases showed that both Cys-type and Ser-type sulfatase genes tend to be contiguous with their putative modifying factor-encoding genes, SUMF1-homologs or AtsB-homologs, respectively (12Go,23Go), suggesting the presence of sulfatase operons.

We selected 69 eubacterial and 14 archaeal organisms, one for each genus with at least one completely sequenced genome, to perform exhaustive neighborhood analyses of prokaryotic sulfatase genes. We first searched the 83 selected genomes for the presence of sulfatases, using the sequences of known prokaryotic sulfatases in addition to the sequences of representative eukaryotic sulfatases as queries. The results showed that sulfatase genes are present in 21 Eubacteria, grouped in five phyla (Proteobacteria, Actinobacteria, Bacteroidetes, Planctomycetes and Cyanobacteria) out of the 13 investigated and in one Archaea, Methanosarcina acetivorans, a member of the Euryarchaeota phylum (Fig. 4). The number of sulfatase genes ranges from one to more than 100 genes per species with most species having one to three sulfatases (Fig. 5). Eubacteria contain either Cys-type or Ser-type sulfatases, whereas the archaeal M. acetivorans have only Cys-type sulfatases. Interestingly, three bacterial species (Escherichia coli, Yersinia pestis and Vibrio vulnificus) contain both types of sulfatases (Fig. 4).



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  		Figure 4. Distribution of sulfatase and sulfatase modifying factor genes within the evolutionary tree of fully sequenced eubacterial species. All the investigated species are shown. Sulfatase genes are present in the following phyla: Proteobacteria, Actinobacteria, Bacteroidetes, Planctomycetes and Cyanobacteria. Bacterial species and phyla that lack sulfatase genes are in gray. The following species were investigated: Aa, Aquifex aeolicus; Ag, Agrobacterium tumefaciens; Ba, Buchnera aphidicola; Bb, Borrelia burgdorferi; Bj, Bradyrhizobium japonicum; Bm, Brucella melitensis; Bs, Bacillus subtilis; Bl, Bifidobacterium longum; Bp, Bordetella parapertussis; Bt, Bacteroides thetaiotaomicron; Ca, Clostridium acetobutylicum; Cb, Coxiella burnetii; Ce, Corynebacterium efficiens; Cj, Campylobacter jejuni; Cc, Caulobacter crescentus; Cp, Chlamydophila pneumoniae; Ct (Chlamidiae), Chlamydia trachomatis; Ct (Chlorobi), Chlorobium tepidum; Cv, Chromobacterium violaceum; Dr, Deinococcus radiodurans; Ec, Escherichia coli; Ef, Enterococcus faecalis; Fn, Fusobacterium nucleatum; Gs, Geobacter sulfurreducens; Gv, Gloeobacter violaceus; Hi, Haemophilus influenzae; Hp, Helicobacter pylori; Ll, Lactococcus lactis; Li (Spirochaetes), Leptospira interrogans; Li (Firmicutes), Listeria innocua; Ml, Mesorhizobium loti; Mp, Mycoplasma pneumoniae; Mt, Mycobacterium tuberculosis; Ne, Nitrosomonas europaea; Nm, Neisseria meningitides; No, Nostoc sp.; Oi, Oceanobacillus iheyensis; Oy, Onion yellows phytoplasma; Pa, Pseudomonas aeruginosa; Pg, Porphyromonas gingivalis; Pi, Pirellula sp.; Pl, Photorhabdus luminescens; Pm (Proteobacteria), Pasteurella multocida; Pm (Cyanobacteria), Prochlorococcus marinus; Rc, Rickettsia conorii; Rp, Rhodopseudomonas palustris; Rs, Ralstonia solanacearum; Sa, Staphylococcus aureus; Sc, Streptomyces coelicolor; Se, Salmonella enterica; Sf, Shigella flexneri; Sm, Sinorhizobium meliloti; So, Shewanella oneidensis; Sp, Streptococcus pneumoniae; Sy, Synechococcus sp.; Te, Thermosynechococcus elongates; Tm, Thermotoga maritime; Tp, Treponema pallidum; Tt, Thermoanaerobacter tengcongensis; Tw, Tropheryma whipplei; Uu, Ureaplasma urealyticum; Vv, Vibrio vulnificus; Ws, Wolinella succinogenes; Xa, Xanthomonas axonopodis; Xf, Xylella fastidiosa; Yp, Yersinia pestis.

 


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  		Figure 5. Distribution of Cys-type and Ser-type sulfatases in representative prokaryotic species from six Eubacterial and Archaeal phyla (Proteobacteria, Actinobacteria, Bacteroidetes, Planctomycetes, Cyanobacteria and Euryarchaeota).

 
We searched the selected prokaryotic genomes for the presence of sulfatase modifying factor genes using various previously reported (12Go,21Go–23Go,36Go) SUMF1 and AtsB amino acid sequences. In most cases, the analyses revealed that modifying factor genes are physically associated to sulfatase genes, suggesting the presence of sulfatase operons (Fig. 6) (all the cases we analyzed are shown as Online Supporting Data at http://sulfabase.tigem.it). SUMF1 homologous genes flank Cys-type sulfatase genes in 75% of the cases, whereas 35% of the identified AtsB genes flank Ser-type sulfatase genes. Unexpectedly, in some bacterial species, AtsB genes were found to be physically associated to Cys-type sulfatase genes (46% of cases) (Fig. 6 and Online Supporting Data at http://sulfabase.tigem.it). These data strongly suggest a previously unsuspected functional association between the AtsB-type modifying factor and Cys-type sulfatases, a possibility that is reinforced by the observation that no SUMF1 homolog is detectable within the genomes of bacteria carrying both Cys-type sulfatase and AtsB genes.



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  		Figure 6. Locus neighborhood analysis of prokaryotic genes encoding SUMF1 and AtsB homologs. Percentages refer to a total of 12 SUMF1 and 15 AtsB genes identified in the examined species. SUMF1 genes are found in association with Cys-type sulfatase genes, whereas AtsB genes are associated with both Ser-type and Cys-type sulfatase genes. Graphs representing all single gene association cases are reported as Online Supporting Data at http://sulfabase.tigem.it.

 
A genomic analysis of PMH genes showed that their presence is restricted to some bacteria from the Alpha- and Gamma-Proteobacteria subphyla, some of which are provided with sulfatase and SUMF1 genes (all identified PMH genes are reported at http://sulfabase.tigem.it). Neighborhood analyses of PMH genes showed that they never flank SUMF1 genes in the examined genomes: in these species, the identified SUMF1 homologs are rather found to associate with Cys-type sulfatase genes in distant loci from PMHs. Moreover, in at least one case (Rhodopseudomonas palustris), a PMH gene is present in a genome that lacks any sulfatase modifying factors. These data suggest that the cysteine at the active site of PMHs does not undergo post-translational conversion, which can explain the specificity of the reactions catalyzed by sulfatases and PMHs and their lack of overlap, as previously reported (31Go).

Finally, our analysis showed that no other gene is associated with any sulfatase genes in more than one bacterial genome, with the exception of only few cases in which Cys-type sulfatase genes are associated with genes encoding the three subunits of an ABC-type permease (data not shown). This would suggest that there are no further modifying factors of bacterial sulfatases other than SUMF1 and AtsB. However, a few species (R. palustris, Brucella melitensis and Agrobacterium tumefaciens; see Online Supporting Data at http://sulfabase.tigem.it) lack both SUMF1 and AtsB, despite the presence of Cys-type sulfatase genes within their genomes. These exceptions are reminiscent of C. elegans as well as of several fully sequenced fungal species we investigated (Schizosaccharomyces pombe, Neurospora crassa, Debaryomyces hansenii, Kluyveromyces lactis and Yarrowia lipolytica; see Online Supporting Data at http://sulfabase.tigem.it), all organisms harboring one or two sulfatase genes but lacking any obvious modifying factor. These species will require a detailed biochemical analysis to establish whether post-translational modification of the cysteine residue at the active site actually occurs.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 ECR Analysis
 REFERENCES
 
World-wide genome sequencing projects and massive gene annotation have shifted research efforts toward post-genomic molecular biology, leading to the development of new approaches to study gene functions (37Go). In the last few years, several studies have provided evidence of the usefulness of intra- and inter-genomic investigation to begin solving complex biological problems that are arduous to tackle by the traditional molecular techniques (38Go–42Go).

Here, we used a genomic approach to investigate sulfatases and their relationship with sulfatase modifying factors in humans and many model systems. Our analysis resulted in several novel biological findings that can be used as guidelines for directing genetic and biochemical research on sulfatase activation and function.

We first completed the catalog of mammalian sulfatases, revealing that it comprises 17 human, 17 dog and 14 rodent members, including four novel sulfatases (ARSH, ARSI, ARSJ and ARSK). We identified murine and dog orthologous genes for each human sulfatase, with the exception of ARSD, ARSF and ARSH, which are present in both human and dog genomes but not in rat and mouse. These additional genes are similar to each other and are clustered with ARSE on the distal short arm of the X chromosome (Xp22.3) close to the human pseudoautosomal region. The cluster is clearly the result of a series of recent duplications occurred during mammalian evolution. Sequence comparison and evolutionary analyses suggest that ARSE was the ancestor gene of the cluster.

Importantly, mutations in ARSE are responsible for X-linked CDPX (20Go), whereas no mutation leading to a disease has been reported so far for any of the other sulfatase genes of the cluster, suggesting that the function of these sulfatases may be redundant. The generation of a murine Arse knockout may provide insights into this matter.

A global analysis of the amino acid sequences of human sulfatases led to the identification of nine ECRs shared by all proteins. The ECR procedure assigns local evolutionary rates by comparing sliding windows of a given length. The optimal length of the window is protein-specific and must be determined as a compromise between the need to maximize the sensitivity of the analysis and to minimize background noise. We established that the analysis performed with a window of 11 amino acids gives a reliable model of the ECR map of sulfatases, in that six out of nine identified ECRs contain all the residues known to be involved in substrate stabilization and hydrolysis. Remarkably, the other three ECRs contain several residues with unknown function that are conserved in all sulfatases. Mutations in some of these residues are associated with different human diseases (Table 2 and references therein), suggesting that they play a common enzymatic role. All the conserved residues identified in sulfatase ECRs are therefore prime candidates for testing in mutagenesis experiments aimed to establish whether non-conservative substitution disrupts sulfatase function.

Defining the evolutionary profiles of sulfatases from mammals, D. melanogaster and C. elegans, showed that the FGly-containing signature is the most conserved segment of mammalian and fly sulfatases when grouped by species but not by sulfatase types. We also found that mammalian and fly signatures show intraspecies sequence convergence at some residues. In these organisms, FGly formation seems to be performed by a single modifying system, which involves SUMF1 as the major (or only) component (21Go,22Go). On the contrary, C. elegans lacks a SUMF1 homolog, and its sulfatase signatures show a significant lower degree of convergence with respect to mammals and fruitfly. The signature convergence observed in mammals and Drosophila could be the result of a specific evolutionary pressure exerted by SUMF1 and aimed to keep its targets recognizable from the remaining proteome. Our analyses showed that no other protein encoded along the examined genomes contains a motif comparable to the signature of sulfatases; furthermore, we observed that the few non-sulfatase proteins containing an evolutionarily conserved CxPSR motif (CxP[SA]R in Drosophila) are not targeted to the ER, therefore excluding the possibility that they can be processed by the modifying system. These data clearly support the conclusion that in these species sulfatases are the only likely cellular targets of the FGly-generating system. This result in humans is consistent with the MSD phenotype, which appears to result from the association of the features of each single sulfatase deficiency. Additional analyses showed that there is a lower representation of the amino acid motifs CxxSR, CxPxR, etc. among ER proteins compared with proteins that do not enter the ER (data not shown). Taken together, our data suggest the presence of an evolutionary mechanism that counter-selects sulfatase-signature-like sequences within non-sulfatase proteins targeted to the ER, likely aimed at avoiding interference with the FGly-generating system.

An exclusive relationship between sulfatases and sulfatase modifying factors resulted also from gene association studies on prokaryotic genomes. This analysis revealed that, in ~75% of the cases, SUMF1 and AtsB modifying factor genes are physically associated with sulfatase genes at the same genomic locus, indicating functional coupling. In addition, no other genes but sulfatases are associated with SUMF1 or AtsB genes in a significant number of species, strongly suggesting that prokaryotic sulfatases are the only targets of their modifying factors.

The physical association between SUMF1 genes and Cys-type sulfatase genes in bacteria is remarkable. Retrospectively, this information could have been used to identify the human SUMF1 gene rather than using the genetic (22Go) or biochemical (21Go) approaches. Unexpectedly, we also found physical association between AtsB genes and Cys-type sulfatase genes in prokaryotic species lacking SUMF1, strongly suggesting that in these species AtsB is involved in the modification of Cys-type sulfatases. This is an important departure from the current paradigm of FGly formation as to date, post-translational generation of FGly from cysteine was believed to differ from the reaction of serine conversion (12Go,36Go).

In addition to SUMF1 and AtsB, there is evidence of a third system to perform cysteine to FGly modification. This comes from the genomes of a few bacterial species and of fungi as well as C. elegans, which have sulfatase genes in their genomes but lack SUMF1 and AtsB homologous genes. These data open the possibility that an additional FGly-generating system may exist even in mammals. This putative system may participate, in concert with SUMF1, to the modification of sulfatases and may explain the residual sulfatase activities in patients with MSD (2Go).

From a methodological point of view, it is interesting to observe how the different approaches we used to investigate the relationship between sulfatases and sulfatase modifying factors could be regarded as a reflection of the different evolutionarily strategies that genomes themselves adopted to create and maintain such a relationship—sequence convergence at the site to be modified in Eukaryotes and physical/functional gene association in Prokaryotes. Our study proves that the comparative genomic analysis of functionally associated gene families can provide important information both on their evolution and function. To our knowledge, this work is the first study of functionally associated gene families to span the three domains of life (Eukarya, Eubacteria and Archaea) and therefore can be used as a general model for in-depth analysis of concomitant gene functions.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
ECR Analysis
 REFERENCES
 
Genomic analyses
Human, dog, mouse, rat, D. melanogaster and C. elegans genomes were searched for sulfatase genes using TBLASTN and BLAT at NCBI (http://www.ncbi.nih.gov/BLAST/) and UCSC (http://genome.ucsc.edu/), respectively, using the amino acid sequences of known sulfatases as queries. The retrieved genomic sequences were compared with the available cDNA/EST sequences to infer the gene structures. For genes that lacked a transcript counterpart in public databases, we first identified their closest putative ortholog (a homologous gene from another species which derives from the same single ancestor gene that was present in the last common ancestor of both species) or paralog (a homologous gene derived from intra-species gene duplications of the same ancestor gene); then, we performed a careful manual comparison of the genomic sequences with these retrieved sequences using pairwise TBLASTN and TBLASTX, looking for splicing donor and acceptor signals to define the gene architectures. Comparison of human, dog, mouse and rat orthologous sulfatase genes showed that 100% of splicing acceptor and donor sites were conserved at the same positions in all species, i.e. the gene structure of all sulfatase orthologous genes is identical at the single codon level. Orthology relationships among all eukaryotes sulfatases described in this work were assigned by constructing phylogenetic trees with CLUSTALW (43Go) (data not shown). All chromosomal positions reported in this work refer to the following genome releases: Homo sapiens, May 2004 assembly (NCBI Build 35); Canis familiaris, July 2004 assembly (Broad Institute v1.0); Mus musculus, May 2004 assembly (NCBI Build 33); Rattus norvegicus, June 2003 assembly (Baylor College of Medicine HGSC v3.1). Prokaryotic genomes were searched for sulfatase and sulfatase modifying factor genes with BLASTP at the Genome Information Broker genome browser (http://gib.genes.nig.ac.jp/) using the amino acid sequences of known prokaryotic and eukaryotic sulfatases and SUMF1 and AtsB proteins as queries. The flanking five genes located at each side of all identified sulfatase and sulfatase modifying factor genes were also analyzed, looking for the presence of putative sulfatase operons and/or conserved neighbors across different genomes. All analyses on prokaryotic genomes were performed using the protein sequences and the start codons as annotated at the Genome Information Broker.


   ECR Analysis
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 ECR Analysis
REFERENCES
 
Local evolution rates over the amino acid sequences of the 17 human sulfatases were estimated using the evolution–structure– function method (27Go). This analysis requires an accurate reconstruction of the homology relationships among the entire length of all analyzed peptides, as well as an estimate of their evolutionary relationships. In brief, a direct multiple alignment analysis failed to correctly align the peptide sequences of all human sulfatases, possibly because of the great sequence divergence that is detectable between some sulfatase set members. We then performed pairwise alignment of all peptides to identify the reciprocal corresponding segments, which were marked by linker (artificial 10- or 20-long amino acid sequences) insertion. A total of seven linkers per sequence were required to force all sequences to align correctly in a full multiple alignment, which was performed with MULTALIN (44Go). After removal of linkers, all positions containing a sequence gap in >35% of sulfatases were also removed to avoid the presence of non-informational sites in the subsequent phylogenetic and ECR analyses. We built the phylogenetic tree of human sulfatases using the CLUSTALW software (43Go) and holding its branching pattern constant, we calculated the number of substitutions per site in each 11-residue-wide window over the entire amino acid alignment using CODEML (45Go). Finally, rate values were derived by first dividing the number of substitutions per site in each window by the average of all windows of the same size (yielding the ‘relative rate’), and then smoothing the relative rates using a seven-position-wide moving window arithmetic average. The evolutionary profile was plotted as a function of alignment position in a two-dimensional array. Scanning the array from the bottom (minimum) to top (maximum) yielded a ranked list of local minima that define as many ECRs, whose maximum extents are bounded by closest previous and following positions where the second derivative is zero.

Generation of sulfatase signature logos
Logo representations are used to visualize the information content associated with each position of a given motif shared by related sequences (32Go,33Go). In the graphical representation, the overall height of each position is correlated to the conservation at that position (expressed in bits), whereas the relative sizes of the symbols within a position indicate their relative frequencies. Reported values were computed as the rate between the information content of the given position and the information content of unvarying positions within the motif. Logo analyses were performed at the Berkeley Structural Genomics Center (http://weblogo.berkeley.edu/).

Peptide analysis
Examined eukaryotic proteomes were downloaded from the Ensembl FTP site at http://www.ensembl.org/Download/. Amino acid motifs of interest were searched using FUZZPRO from the Jemboss software package (http://www.hgmp.mrc.ac.uk/Software/EMBOSS/Jemboss/index.html). Predictions of subcellular localization were performed using the programs TargetP (46Go), available at the Technical University of Denmark DTU (http://www.cbs.dtu.dk/services/TargetP/) and LOCtarget (47Go), available at the Columbia University Bioinformatic Center (http://cubic.bioc.columbia.edu/).

Evolutionary analyses
Because synonymous substitutions do not alter the encoded protein, they are generally assumed to be nearly neutral with respect to selection. This allows using the statistic KS (the estimated mean number of synonymous substitutions per synonymous site) to gauge evolutionary time (48Go). We measured, for each pair of genes from the human sulfatase cluster at Xp22.3 (namely ARSD, ARSE, ARSF and ARSH), synonymous nucleotide divergence between coding regions after removal of all the sequence gaps that resulted from a multiple alignment. In the present context, KS values provide a measure of the evolutionary time that has elapsed as each sulfatase started to diverge after duplication. The inferred order of gene duplication was confirmed by constructing phylogenetic trees (CLUSTALW) (43Go) using the both nucleotide and amino acid sequences of the examined genes and rat Arse as an out-group (data not shown). The evolutionary distances among bacterial species were calculated at the NeuroGadget Inc. website (http://www.neurogadgets.com/bioinf18.php) as the mean values of the distances of all the proteins shared by all examined species, with a BLASTP threshold of 10–50. The evolutionary tree was then generated at the Pasteur Institute web server using the Bionj software (http://bioweb.pasteur.fr/seqanal/interfaces/bionj-simple.html).


   ACKNOWLEDGEMENTS
 
We thank Alberto Auricchio, Gilda Cobellis, Maria Pia Cosma, Thomas Dierks and Anthony Fedele for helpful suggestions and the critical reading of this manuscript. This work was supported by an institutional grant by the Italian Telethon Foundation.

Conflict of Interest statement. None declared.


   FOOTNOTES
 
{dagger} AY875937–AY875940; BN000735–BN000767 Back


   REFERENCES
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 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 ECR Analysis
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