Structure of PARP1

PARP (PARP1 antibody) is composed of four domains of interest: a DNA-binding domain, a caspase-cleaved domain , an auto-modification domain, and a catalytic domain. Two zinc finger motifs make up the DNA-binding domain. When damaged DNA (base pair-excised) is present, the DNA-binding domain binds to it and causes a conformational shift. This binding has been proven to occur independently of the other domains. This is crucial in a programmed cell death paradigm based on the suppression of PARP cleavage by caspases. After catalysis, the auto-modification domain is responsible for freeing the protein from the DNA. In addition, it is involved in cleavage-induced inactivation.

The modular domain design of poly(ADP-ribose) polymerase-1 (PARP-1) (ADP, adenosine diphosphate) connects DNA damage sensing to poly(ADP-ribosyl)ation activity through a poorly understood mechanism. The crystal structure of a DNA double-strand break in conjunction with human PARP-1 domains required for activation is described here (Zn1, Zn3, WGR-CAT). PARP-1 interacts with DNA as a monomer, and the interaction with DNA damage collapses the PARP-1 domains, explaining the high propensity for auto modification. The Zn1, Zn3, and WGR domains all bind to DNA establishing an interdomain network that connects the DNA damage interface to the catalytic domain (CAT). The structural abnormalities caused by PARP-1’s DNA damage-induced conformation destabilize the CAT.