InterPro: IPR012317 Poly(ADP-ribose) polymerase, catalytic domain

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes present in eukaryotes, which catalyze the poly(ADP-ribosyl)ation of a limited number of proteins involved in chromatin architecture, DNA repair, or in DNA metabolism, including PARP itself. PARP, also known as poly(ADP-ribose) synthetase and poly(ADP-ribose) transferase, transfers the ADP-ribose moiety from its substrate, nicotinamide adenine dinucleotide (NAD), to carboxylate groups of aspartic and glutamic residues. Whereas some PARPs might function in genome protection, others appear to play different roles in the cell, including telomere replication and cellular transport. PARP-1 is a multifunctional enzyme. The polypeptide has a highly conserved modular organization consisting of an N-terminal DNA-binding domain, a central regulating segment, and a C-terminal or F region accommodating the catalytic centre. The F region is composed of two parts: a purely alpha-helical N- terminal domain (alpha-hd), and the mixed alpha/beta C-terminal catalytic domain bearing the putative NAD binding site. Although proteins of the PARP family are related through their PARP catalytic domain, they do not resemble each other outside of that region, but rather, they contain unique domains that distinguish them from each other and hint at their discrete functions. Domains with which the PARP catalytic domain is found associated include zinc fingers, SAP, ankyrin, BRCT, Macro, SAM, WWE and UIM domains [1, 2, 3].

The alpha-hd domain is about 130 amino acids in length and consists of an up-up-down-up-down-down motif of helices. It is thought to relay the activation signal issued on binding to damaged DNA [4, 5]. The PARP catalytic domain is about 230 residues in length. Its core consists of a five-stranded antiparallel beta-sheet and four-stranded mixed beta-sheet. The two sheets are consecutive and are connected via a single pair of hydrogen bonds between two strands that run at an angle of 90 degrees. These central beta-sheets are surrounded by five alpha-helices, three 3(10)-helices, and by a three- and a two-stranded beta-sheet in a 37-residue excursion between two central beta-strands [4, 5]. The active site, known as the 'PARP signature' is formed by a block of 50 amino acids that is strictly conserved among the vertebrates and highly conserved among all species. The 'PARP signature' is characteristic of all PARP protein family members. It is formed by a segment of conserved amino acid residues formed by a beta-sheet, an alpha-helix, a 3(10)-helix, a beta-sheet, and an alpha-helix [3].