In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily

Poly(ADP-ribose) polymerases (PARPs), also known as the diptheria-toxin like ADP-ribosyltransferases, are a superfamily of 17 enzymes which are involved in many cellular pathways. First discovered in 1963, their function has expanded to roles including DNA repair, chromatin modulation, transcription signalling, RNA processing, cell stress responses and host-virus interactions (1-4). Each PARP contains multiple functional domains that contribute to their overall physiological role and PARPs are subcategorized based on their predominant functional domain. These include the DNA dependent PARPs, tankyrases, CCCH-Zn finger-PARPs, macroPARP and the other category (Table1) (5-10). However, all PARPs share a highly homologous catalytic (ART) domain, which is responsible for their shared function of adding moieties of ADP-ribose (ADPr) onto select target proteins using NAD⁺ as a substrate (2).

Table 1. Key domains, lengths and enzyme activity for the poly(ADP-ribose) polymerase family members.

Subclass	PARP family member	Amino acid length	Enzymatic activity	Key functional domains
DNA dependent	PARP1	1014	PAR	ART, WGR, zinc fingers, NLS and BRCT
	PARP2	570	PAR	ART, NLS and WGR
	PARP3	570	PAR	ART, NLS and WGR
CCCH Zn finger	PARP7	657	MAR	ART, zinc-fingers and WWE
	PARP12	701	MAR	ART and zinc-fingers and WWE
	PARP13	902	Inactive	ART, zinc-fingers, NLS and WWE
Tankyrases	PARP5a	1327	PAR	ART, SAM and 24 Ankyrin repeats
	PARP5b	1166	PAR	ART, SAM and 24 Ankyrin repeats
Macro-PARPs	PARP9	854	Inactive	ART, macro1, macro2
	PARP14	1801	MAR	ART, macro1, macro2, macro3, WWE, RRM
	PARP15	444	MAR	ART, macro1, macro2
Other	PARP4	1724	PAR	ART, VIT, vWFA, WGR, NLS and BRCT
	PARP6	322	MAR	ART
	PARP8	854	MAR	ART
	PARP10	1025	MAR	ART, RRM, UIM, transmembrane
	PARP11	331	MAR	WWE, ART
	PARP16	630	MAR	WGR, ART and transmembrane

Data taken from (8,10).

Despite the nomenclature ‘poly (ADP-ribose) polymerase’, only the first six enzymes are capable of this namesake poly ADP-ribosylate (PAR) function (11). PARP1-PARP5b contains the classical and conserved NAD⁺ binding HIS-TYR-GLU (H-Y-E) triad within the nicotinamide-binding pocket (Table2). This triad is associated with PAR activity, which is also seen in the diptheria toxin, an H-Y-E containing protein secreted by the Corynebacteriuym diptheria (12). The alternative nomenclature to the PARP family, the diphtheria-toxin like ADP-ribosyltransferase, comes in part from this close relation between PARPs and the diptheria toxin (11). In humans, these...