D
IPR049296

PARP1-like, PADR1 domain, N-terminal helical subdomain

InterPro entry
Short namePARP1-like_PADR1_N

Description

This entry represents de N-terminal helical region of PADR1 zinc-binding domain found in poly(ADP-ribose) polymerase-1 (PARP-1) from human and its homologues. The PADR1, known as the third zinc-binding domain (Zn3) localises between the N-terminal PARP-type zinc fingers (Zn1 and Zn2) and the central BRCT domain; it is involved in protein-protein interactions that orchestrate PARP-1 activation and are critical to the DNA-dependent stimulation of PARP-1
[3, 5, 2, 4, 1]
.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-associated enzyme involved in multiple cellular processes including DNA repair, cell cycle control, apoptotic signalling, and transcriptional regulation. Stimulated by binding to nicked DNA, PARP-1 catalyses 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 that can be generally described in three major segments representing the biochemical activities and functional roles of the enzyme: the DNA-binding domain (DBD), the automodification domain which contains a BRCT fold, and the catalytic domain, which consists of the helical (HD) and the ART subdomains. The catalytic domain of PARP-1 is located at the C-terminal end of the protein. The DNA-binding domain is located at the N terminus of PARP-1 and contains two zinc fingers that bind to various DNA structures, a nuclear localization signal, 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, referred to as PADR1, located between the N-terminal PARP-type zinc fingers and the central BRCT domain and it is required to mediate interdomain contacts essential for the efficient assembly of PARP-1 domains
[1, 6, 3, 2, 5, 7, 4]
.

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. 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
[3, 2, 5, 7]
.

References

1.Poly(ADP-Ribose) Polymerases in Plants and Their Human Counterparts: Parallels and Peculiarities. Rissel D, Peiter E. Int J Mol Sci 20, E1638, (2019). PMID: 30986964

2.Domain C of human poly(ADP-ribose) polymerase-1 is important for enzyme activity and contains a novel zinc-ribbon motif. Tao Z, Gao P, Hoffman DW, Liu HW. Biochemistry 47, 5804-13, (2008). View articlePMID: 18452307

3.A third zinc-binding domain of human poly(ADP-ribose) polymerase-1 coordinates DNA-dependent enzyme activation. Langelier MF, Servent KM, Rogers EE, Pascal JM. J. Biol. Chem. 283, 4105-14, (2008). View articlePMID: 18055453

4.Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity. Langelier MF, Planck JL, Roy S, Pascal JM. J. Biol. Chem. 286, 10690-701, (2011). View articlePMID: 21233213

5.Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Langelier MF, Planck JL, Roy S, Pascal JM. Science 336, 728-32, (2012). PMID: 22582261

6.Insights into the evolution of the nucleolus by an analysis of its protein domain repertoire. Staub E, Fiziev P, Rosenthal A, Hinzmann B. Bioessays 26, 567-81, (2004). View articlePMID: 15112237

7.Captured snapshots of PARP1 in the active state reveal the mechanics of PARP1 allostery. Rouleau-Turcotte E, Krastev DB, Pettitt SJ, Lord CJ, Pascal JM. Mol Cell 82, 2939-2951.e5, (2022). PMID: 35793673

Cross References

Contributing Member Database Entry
This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.