PROSITE documentation PDOC52007

PADR1 zinc-binding domain profile

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme involved in multiple cellular processes including DNA repair, cell cycle control, apoptotic signaling, and transcriptional regulation. Stimulated by binding to nicked DNA, PARP-1 catalyzes poly(ADP-ribosyl)ation of the acceptor proteins using NAD(+) as a substrate. PARP-1 has a modular architecture composed of multiple, independently folded domains. The PARP-1 polypeptide is generally described in three major segments that represent the biochemical activities and functional roles of the enzyme: the DNA-binding domain (DBD), the automodification domain, and the catalytic domain. The catalytic domain of PARP-1 is located at the C-terminal end of the protein. It contains a WGR motif, which is defined by the conserved Trp, Gly, and Arg residues (see <PDOC51977>). The function of this domain remains uncertain, although it is a possible nucleic acid binding region. The minimal catalytic domain (CAT) is composed of two subdomains, the helical subdomain (HD) and the ART subdomain, which is conserved in other ADP-ribosyl transferases (ARTs), and includes the amino acids involved in catalysis and binding of NAD(+) (see <PDOC51059>). The automodification domain (AD) bears the major sites of automodification and contains a BRCT (BRCA1 C terminus) fold. This fold is present in several DNA repair factors and is frequently found to mediate protein-protein interactions (see <PDOC50172>). The DNA-binding domain is located at the N terminus of PARP-1. The DBD contains two zinc fingers that bind to various DNA structures (see <PDOC00360>), a nuclear localization signal (see <PDOC00015>), and a caspase-3 cleavage site. The two N-terminal zinc fingers of PARP-1 bind to DNA structures to trigger activation of the C-terminal catalytic domain of PARP-1. The DBD of human PARP-1 contains yet a third zinc-binding domain, PADR1, located between the N-terminal PARP-type zinc fingers and the central BRCT domain. The PADR1 zinc-binding domain is involved in protein-protein interactions that orchestrate PARP-1 activation and are critical to the DNA-dependent stimulation of PARP-1. It relays the DNA binding signal from the first two zinc fingers to the catalytic C terminus by helping to establish the active form of the enzyme [1,2,3,4,5].

The fold of the PADR1 zinc-binding domain consists of an N-terminal helical region, a central zinc ribbon fold, and a C-terminal tail (see <PDB:2RIQ>). Three α-helices form a subdomain at the N terminus, with the first helix extending away from the subdomain. The zinc-binding region forms a separate subdomain, making primarily water-mediated contacts with the N-terminal helical subdomain. The zinc-binding subdomain resembles a zinc ribbon fold with four Cys ligands. The spacing between the four Cys residues is strongly conserved among all organisms, following the pattern C-x(2)-C-x(11,12)-C-x(9)-C where C is cysteine and x(n) is the number of amino acids between the Cys residues. The zinc-binding subdomain contains a three-stranded antiparallel β-sheet, with the first pair of zinc ligands located in the loop running over the top of the sheet. The other pair of zinc ligands is centrally located within β-strands, a result of a long (nine-amino acid) insertion between the third and fourth cysteines. An α-helix on the C-terminal tail of the PADR1 zinc-binding domain contributes to the fold of the N-terminal helical region, and the remainder of the C terminus extends away from the N-terminal subdomain [2,3,4,5].

The profile we developed covers the whole PADR1 zinc-binding domain.