Abstract
BackgroundHuman ART4, carrier of the GPI-(glycosyl-phosphatidylinositol) anchored Dombrock blood group antigens, is an apparently inactive member of the mammalian mono-ADP-ribosyltransferase (ART) family named after the enzymatic transfer of a single ADP-ribose moiety from NAD+ to arginine residues of extracellular target proteins. All known mammalian ART4 orthologues are predicted to lack ART activity because of one or more changes in essential active site residues that make up the R-S-EXE motif. So far, no other function has been detected.ResultsHere we report the identification and characterisation of ART4 in chicken, which to our knowledge is the first true non-mammalian orthologue of a mammalian ART family member. The chicken ART4 gene has the same physical structure as its mammalian counterparts (three coding exons separated by two introns in phase 0 and phase 1, respectively) and maps to a region of conserved linkage synteny on chromosome 1. Its mRNA encodes a 289 amino acid protein with predicted N-terminal signal peptide and C-terminal GPI-anchor sequences and 47% sequence identity to human ART4. However, in striking contrast to its mammalian orthologues, the chicken protein contains an intact R-S-EXE motif. Upon ectopic expression in C-33A cells, recombinant chicken ART4 localized at the cell surface as a GPI-anchored, highly glycosylated protein, which displayed arginine-specific ART activity (apparent Km of the recombinant protein for etheno-NAD+ 1.0 ± 0.18 μM).ConclusionThe avian orthologue of the "acatalytic" mammalian ART4 is a mono-ADP-ribosyltransferase with enzymatic activity comparable to that of other, catalytically active and GPI-anchored members of the mammalian ART family.
Highlights
Human ART4, carrier of the GPI-(glycosyl-phosphatidylinositol) anchored Dombrock blood group antigens, is an apparently inactive member of the mammalian mono-ADPribosyltransferase (ART) family named after the enzymatic transfer of a single ADP-ribose moiety from NAD+ to arginine residues of extracellular target proteins
The avian orthologue of the "acatalytic" mammalian ART4 is a mono-ADPribosyltransferase with enzymatic activity comparable to that of other, catalytically active and GPIanchored members of the mammalian ART family
No evidence for a potential other function has emerged for either of the two "acatalytic" members of the mammalian ART family, except that human ART4 has previously been demonstrated to be identical with the polymorphic Dombrock blood group antigen expressed on erythrocytes as GPIanchored glycoprotein [7,8]
Summary
Human ART4, carrier of the GPI-(glycosyl-phosphatidylinositol) anchored Dombrock blood group antigens, is an apparently inactive member of the mammalian mono-ADPribosyltransferase (ART) family named after the enzymatic transfer of a single ADP-ribose moiety from NAD+ to arginine residues of extracellular target proteins. ART3 and ART4 appear to have lost their catalytic activity, most likely due to the non-conservative substitution of residues in the R-S-EXE motif, which is typically present in the active centre of arginine-specific ARTs [6]. No evidence for a potential other function has emerged for either of the two "acatalytic" members of the mammalian ART family, except that human ART4 has previously been demonstrated to be identical with the polymorphic Dombrock blood group antigen expressed on erythrocytes as GPI (glycosyl-phosphatidylinositol)anchored glycoprotein [7,8]. We and others have shown that expression of the human ART4 gene can be induced by lipopolysaccharide, lipoteichoic acid and peptidoglycan in monocytes and alveolar epithelial cells [9,10,11]
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