Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37756394.
- Also identified by DOI 10.1126/sciadv.adi8291 and PMC identifier 10530080.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that is activated by DNA double-strand breaks. However, ATM is also directly activated by reactive oxygen species, but how oxidative activation is achieved remains unknown. We determined the cryo-EM structure of an H<sub>2</sub>O<sub>2</sub>-activated ATM and showed that under oxidizing conditions, ATM formed an intramolecular disulfide bridge between two protomers that are rotated relative to each other when compared to the basal state. This rotation is accompanied by release of the substrate-blocking PRD region and twisting of the N-lobe relative to the C-lobe, which greatly optimizes catalysis. This active site remodeling enabled us to capture a substrate (p53) bound to the enzyme. This provides the first structural insights into how ATM is activated during oxidative stress.
Medical subject headings
- Oxidative Stress
- Ataxia Telangiectasia Mutated Proteins