Crystal structure of human pFGE, the paralog of the Calpha-formylglycine-generating enzyme.
In eukaryotes, sulfate esters are degraded by sulfatases, which possess a unique Calpha-formylglycine residue in their active site. The defect in post-translational formation of the Calpha-formylglycine residue causes a severe lysosomal storage disorder in humans. Recently, FGE (formylglycine-generating enzyme) has been identified as the protein required for this specific modification. Using sequence comparisons, a protein homologous to FGE was found and denoted pFGE (paralog of FGE). pFGE binds a sulfatase-derived peptide bearing the FGE recognition motif, but it lacks formylglycine-generating activity. Both proteins belong to a large family of pro- and eukaryotic proteins containing the DUF323 domain, a formylglycine-generating enzyme domain of unknown three-dimensional structure. We have crystallized the glycosylated human pFGE and determined its crystal structure at a resolution of 1.86 A. The structure reveals a novel fold, which we denote the FGE fold and which therefore serves as a paradigm for the DUF323 domain. It is characterized by an asymmetric partitioning of secondary structure elements and is stabilized by two calcium cations. A deep cleft on the surface of pFGE most likely represents the sulfatase polypeptide binding site. The asymmetric unit of the pFGE crystal contains a homodimer. The putative peptide binding site is buried between the monomers, indicating a biological significance of the dimer. The structure suggests the capability of pFGE to form a heterodimer with FGE.
Dickmanns
Achim
A
Abteilung Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik, Georg-August-Universität, Justus-von-Liebig Weg 9, D-37077 Göttingen, Germany.
Schmidt
Bernhard
B
Rudolph
Markus G
MG
Mariappan
Malaiyalam
M
Dierks
Thomas
T
von Figura
Kurt
K
Ficner
Ralf
R
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002412:Cations; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013429:Sulfatases / Q000737:chemistry* / Q000502:physiology; D014961:X-Ray Diffraction
D002412:Cations; D004220:Disulfides; D010455:Peptides; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases; D002118:Calcium