Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress

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 H2O2-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.

Automated summary

This study determined the structure of H2O2-activated ATM using cryo-EM, revealing the structural remodeling and active site optimization that occur during oxidative activation of ATM. The captured substrate binding also provides insights into the mechanism of ATM activation during oxidative stress.