Formylglycine-generating sulfatase enzyme

This domain is found in eukaryotic proteins [1] required for post-translational sulphatase modification (SUMF1). These proteins are associated with the rare disorder multiple sulphatase deficiency (MSD) [2]. The protein product of the SUMF1 gene is FGE, formylglycine (FGly),-generating enzyme, which is a sulfatase. Sulfatases are enzymes essential for degradation and remodelling of sulfate esters, and formylglycine (FGly), the key catalytic in the active site, is unique to sulfatases [3]. FGE is localised to the endoplasmic reticulum (ER) and interacts with and modifies the unfolded form of newly synthesised sulfatases. FGE is a single-domain monomer with a surprising paucity of secondary structure that adopts a unique fold which is stabilised by two Ca2+ ions. The effect of all mutations found in MSD patients is explained by the FGE structure, providing a molecular basis for MSD. A redox-active disulfide bond is present in the active site of FGE. An oxidised cysteine residue, possibly cysteine sulfenic acid, has been detected that may allow formulation of a structure-based mechanism for FGly formation from cysteine residues in all sulfatases [4].

Literature references

1. Landgrebe J, Dierks T, Schmidt B, von Figura K; , Gene 2003;316:47-56.: The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro- to eukaryotes. PUBMED:14563551

2. Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A; , Hum Mutat. 2004;23:576-581.: Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. PUBMED:15146462

3. Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG; , Cell. 2005;121:541-552.: Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. PUBMED:15907468

4. Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gartner J; , Hum Mutat. 2008;29:205.: Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. PUBMED:18157819

InterPro entry IPR005532

This entry represents domains that have a structure homologous to the complex alpha/beta topology found in sulphatase-modifying factors (SUMF1). SUMF1 is a paralogue of oxoalanine-generating enzyme, also called C(alpha)-formylglycine generating enzyme (FGE). SUMF1 converts newly synthesized inactive sulphatases to their active form by modifying an active site cysteine residue to oxoalanine. Sulphatases are essential for the degradation of sulphate esters, whose catalytic activity is dependent upon an oxoalanine residue PUBMED:16041070. Defects in SUMF1 or FGE cause multiple sulphatase deficiency (MSD), which leads to the impairment of all sulphatases and to the accumulation of glycoaminoglycans or sulpholipids, causing early infant death PUBMED:17206939, PUBMED:16124866, PUBMED:16174644. Known substrates for SUMF1 are: N-acetylgalactosamine-6-sulphate sulphatase (GALNS), arylsulphatase A (ARSA), steroid sulphatase (STS) and arylsulphatase E (ARSE). SUMF1 occurs in the endoplasmic reticulum or its lumen.

This domain is also found in a few methyltransferases and protein kinases.

External database links

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

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Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

This page displays the phylogenetic tree for this family. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

HMM information

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the MSD group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FGE-sulfatase domain has been found.