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TitleStructural insights into the activation of ataxia-telangiectasia mutated by oxidative stress.
Journal, issue, pagesSci Adv, Vol. 9, Issue 39, Page eadi8291, Year 2023
Publish dateSep 29, 2023
AuthorsAnna C Howes / Olga Perisic / Roger L Williams /
PubMed AbstractAtaxia-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 ...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 HO-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.
External linksSci Adv / PubMed:37756394 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 3.3 Å
Structure data

17265

8oxm

EMDB-17265, PDB-8oxm:
ATM(Q2971A) activated by oxidative stress in complex with Mg AMP-PNP and p53 peptide
Method: EM (single particle) / Resolution: 3.3 Å

17266

8oxo

EMDB-17266, PDB-8oxo:
ATM(Q2971A) dimeric C-terminal region activated by oxidative stress in complex with Mg AMP-PNP and p53 peptide
Method: EM (single particle) / Resolution: 3.0 Å

17267

8oxp

EMDB-17267, PDB-8oxp:
ATM(Q2971A) in complex with Mg AMP-PNP
Method: EM (single particle) / Resolution: 2.6 Å

17268

8oxq

EMDB-17268, PDB-8oxq:
ATM(Q2971A) dimeric C-terminal region in complex with Mg AMP-PNP
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Ataxia-Telangiectasia Mutated / ATM / kinase / oxidative stress / p53

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