NAD⁺ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains.

ABSTRACT: PARP-1 cleaves NAD⁺ and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD⁺ analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD⁺ binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery. Our findings reveal a two-

SUBMITTER: Langelier MF 

PROVIDER: S-EPMC5829251 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature