InterPro domain: IPR043472

The Macro or A1pp domain is a module of about 180 amino acids which can bind ADP-ribose (an NAD metabolite) or related ligands. Binding to ADP-ribose could be either covalent or non-covalent [ 1 ]: in certain cases it is believed to bind non-covalently [ 2 ]; while in other cases (such as Aprataxin) it appears to bind both non-covalently through a zinc finger motif, and covalently through a separate region of the protein [ 3 ]. The domain was described originally in association with ADP-ribose 1''-phosphate (Appr-1''-P) processing activity (A1pp) of the yeast YBR022W protein [ 4 ]. The domain is also called Macro domain as it is the C-terminal domain of mammalian core histone macro-H2A [ 5 , 6 ]. Macro domain proteins can be found in eukaryotes, in (mostly pathogenic) bacteria, in archaea and in ssRNA viruses, such as coronaviruses [ 7 , 8 ], Rubella and Hepatitis E viruses. In vertebrates the domain occurs e.g. in histone macroH2A, in predicted poly-ADP-ribose polymerases (PARPs) and in B aggressive lymphoma (BAL) protein. The macro domain can be associated with catalytic domains, such as PARP, or sirtuin. The Macro domain can recognise ADP-ribose or in some cases poly-ADP-ribose, which can be involved in ADP-ribosylation reactions that occur in important processes, such as chromatin biology, DNA repair and transcription regulation [ 9 ]. The human macroH2A1.1 Macro domain binds an NAD metabolite O-acetyl-ADP-ribose [ 10 ]. The Macro domain has been suggested to play a regulatory role in ADP-ribosylation, which is involved in inter- and intracellular signaling, transcriptional regulation, DNA repair pathways and maintenance of genomic stability, telomere dynamics, cell differentiation and proliferation, and necrosis and apoptosis.

The 3D structure of the SARS-CoV Macro domain has a mixed alpha/beta fold consisting of a central seven-stranded twisted mixed beta sheet sandwiched between two alpha helices on one face, and three on the other. The final alpha-helix, located on the edge of the central beta-sheet, forms the C terminus of the protein [ 11 ]. The crystal structure of AF1521 (a Macro domain-only protein from Archaeoglobus fulgidus) has also been reported and compared with other Macro domain containing proteins. Several Macro domain only proteins are shorter than AF1521, and appear to lack either the first strand of the beta-sheet or the C-terminal helix 5. Well conserved residues form a hydrophobic cleft and cluster around the AF1521-ADP-ribose binding site [ 12 , 12 , 12 , 12 ].

Aminopeptidases are exopeptidases involved in the processing and regular turnover of intracellular proteins, although their precise role in cellular metabolism is unclear [ 12 , 13 ].

Leucine aminopeptidases cleave leucine residues from the N-terminal of polypeptide chains; in general they are involved in the processing, catabolism and degradation of intracellular proteins [ 14 , 15 , 15 ]. Leucyl aminopeptidase forms a homohexamer containing two trimers stacked on top of one another [ 15 ]. Each monomer binds two zinc ions. The zinc-binding and catalytic sites are located within the C-terminal catalytic domain [ 15 ]. Leucine aminopeptidase has been shown to be identical with prolyl aminopeptidase ( 3.4.11.5 ) in mammals [ 15 ].

The N-terminal domain of these proteins has been shown in Escherichia coli PepA to function as a DNA-binding protein in Xer site-specific recombination and in transcriptional control of the carAB operon [ 16 , 17 ].

This superfamily represents the Macro domain as well as the N-terminal domain of Leucine aminopeptidase.

1. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol. Mol. Biol. Rev. 70, 789-829
2. Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites. J. Mol. Biol. 385, 212-25
3. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81-5
4. A biochemical genomics approach for identifying genes by the activity of their products. Science 286, 1153-5
5. The WWE domain: a common interaction module in protein ubiquitination and ADP ribosylation. Trends Biochem. Sci. 26, 273-5
6. The crystal structure of AF1521 a protein from Archaeoglobus fulgidus with homology to the non-histone domain of macroH2A. J. Mol. Biol. 330, 503-11
7. The ADP-ribose-1''-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. J. Gen. Virol. 92, 1899-1905
8. The coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog. 15, e1007756
9. The macro domain is an ADP-ribose binding module. EMBO J. 24, 1911-20
10. Splicing regulates NAD metabolite binding to histone macroH2A. Nat. Struct. Mol. Biol. 12, 624-5
11. Structural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J. Virol. 80, 8493-502
12. Leucine aminopeptidase from Arabidopsis thaliana. Molecular evidence for a phylogenetically conserved enzyme of protein turnover in higher plants. Eur. J. Biochem. 205, 425-31
13. Molecular structure of leucine aminopeptidase at 2.7-A resolution. Proc. Natl. Acad. Sci. U.S.A. 87, 6878-82
14. Bacterial aminopeptidases: properties and functions. FEMS Microbiol. Rev. 18, 319-44
15. Structural and immunological evidence for the identity of prolyl aminopeptidase with leucyl aminopeptidase. Biochem. Biophys. Res. Commun. 178, 1459-64
16. X-ray structure of aminopeptidase A from Escherichia coli and a model for the nucleoprotein complex in Xer site-specific recombination. EMBO J. 18, 4513-22
17. Mutational analysis of Escherichia coli PepA, a multifunctional DNA-binding aminopeptidase. J. Mol. Biol. 302, 411-26