{PDOC52007} {PS52007; PADR1} {BEGIN} ************************************* * 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 ). 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 ). 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 ). 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 ), a nuclear localization signal (see ), 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 ). Three alpha-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 beta-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 beta-strands, a result of a long (nine-amino acid) insertion between the third and fourth cysteines. An alpha-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. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: September 2022 / First entry. [ 1] Staub E., Fiziev P., Rosenthal A., Hinzmann B. "Insights into the evolution of the nucleolus by an analysis of its protein domain repertoire." Bioessays 26:567-581(2004). PubMed=15112237; DOI=10.1002/bies.20032 [ 2] Langelier M.-F., Servent K.M., Rogers E.E., Pascal J.M. "A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation." J. Biol. Chem. 283:4105-4114(2008). PubMed=18055453; DOI=10.1074/jbc.M708558200 [ 3] Tao Z., Gao P., Hoffman D.W., Liu H.-W. "Domain C of human poly(ADP-ribose) polymerase-1 is important for enzyme activity and contains a novel zinc-ribbon motif." Biochemistry 47:5804-5813(2008). PubMed=18452307; DOI=10.1021/bi800018a [ 4] Langelier M.-F., Planck J.L., Roy S., Pascal J.M. "Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1." Science 336:728-732(2012). PubMed=22582261; DOI=10.1126/science.1216338 [ 5] Rouleau-Turcotte E., Krastev D.B., Pettitt S.J., Lord C.J., Pascal J.M. "Captured snapshots of PARP1 in the active state reveal the mechanics of PARP1 allostery." Mol. Cell. 82:2939-2951.e5(2022). PubMed=35793673; DOI=10.1016/j.molcel.2022.06.011 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}