Poly(ADP-ribose) polymerases (PARP) (EC 220.127.116.11) are a family of enzymes
present in eukaryotes which catalyzes 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)
synthase 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
center. The F region is composed of two parts: a purely α-helical N-terminal domain (α-hd), and the mixed α/β 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 to which the PARP catalytic domain is found associated with include
zinc fingers (see <PDOC00360>), SAP (see <PDOC50800>), ankyrin (see
<PDOC50088>), BRCT (see <PDOC50172>), Macro domain, SAM (see <PDOC50105>), WWE
(see <PDOC50918>) and UIM (see <PDOC50330>) [1,2,3].
The α-hd domain is ~130 amino acids in length and consists of an up-up-down-up-down-down motif of helices (see <PDB:1PAX> and <PDB:1GS0>). It is
thought to relay the activation signal issued on binding to damaged DNA [4,5].
The PARP catalytic domain is ~230 residues in length (see <PDB:1PAX> and
<PDB:1GS0>). Its core consists of a five-stranded antiparallel β-sheet and
four-stranded mixed β-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 degree. These central β-sheets are surrounded by five α-helices, three 3(10)-helices, and by a three- and a two-stranded β-sheet in
a 37-residue excursion between two central β-strands [4,5]. The active
site, known as the 'PARP signature' is formed by a block of 50 amino acids,
the 'PARP signature', that are 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 β-sheet, an α-helix, a 3(10)-helix, a β-sheet, and an α-helix .
Some proteins known to belong to the PARP family are listed below [2,3]:
- PARP-1. It is involved in the cellular response to DNA damage.
- PARP-3. It is a core component of the centrosome and is preferentially
associated with the daughter centriole at all stages of the cell cycle.
- PARP-4 or VPARP. It is associated with vault particles, a cytoplasmic
ribonucleoprotein complex that associates two other highly conserved
proteins, major vault protein (MVP) and telomerase-associated protein
(TEP1) and an untranslated vault RNA (VRNA).
- PARP-5a or Tankyrase 1 (TRF1-interacting, ankyrin-related ADP-ribose
polymerase). The α-hd domain is replaced in Tankyrase by the SAM
- PARP-5b or Tankyrase 2. It appears to interact with many partners at
discrete subcellular locations, including the Glgi complex and endosomes.
- PARP-7 or TiPARP. It has been identified as a 2,3,7,8-Tetrachlorodibenzo-p-
dioxin (TCDD)-induced mRNA.
- PARP-9 or Bal.
The profiles we developed cover the entire catalytic and α-hd domains.
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