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-Structure paper
Title | Structures of closed and open conformations of dimeric human ATM. |
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Journal, issue, pages | Sci Adv, Vol. 3, Issue 5, Page e1700933, Year 2017 |
Publish date | May 10, 2017 |
Authors | Domagoj Baretić / Hannah K Pollard / David I Fisher / Christopher M Johnson / Balaji Santhanam / Caroline M Truman / Tomas Kouba / Alan R Fersht / Christopher Phillips / Roger L Williams / |
PubMed Abstract | ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, ...ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate-binding site, suggesting that this conformation may represent an inactive or basally active enzyme. The active site is held in this closed conformation by interaction with a long helical hairpin in the TRD3 (tetratricopeptide repeats domain 3) domain of the symmetry-related molecule. The open dimer has two protomers with only a limited contact interface, and it lacks the intermolecular interactions that block the peptide-binding site in the closed dimer. This suggests that the open conformation may be more active. The ATM structure shows the detailed topology of the regulator-interacting N-terminal helical solenoid. The ATM conformational dynamics shown by the structures represent an important step in understanding the enzyme regulation. |
External links | Sci Adv / PubMed:28508083 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.4 - 11.5 Å |
Structure data | EMDB-3668: EMDB-3669: Closed dimer (C1) of human ATM (Ataxia telangiectasia mutated) EMDB-3670: EMDB-3671: EMDB-3672, PDB-5np1: EMDB-3673: |
Source |
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Keywords | SIGNALING PROTEIN / PIKK / kinase / DNA-repair / HEAT-repeats / TRANSFERASE / FAT / MRN |