Electron microscopy and 3D reconstructions reveal that human ATM kinase uses an arm-like domain to clamp around double-stranded DNA.
The human tumor suppressor gene ataxia telangiectasia mutated (ATM) encodes a 3056 amino-acid protein kinase that regulates cell cycle checkpoints. ATM is defective in the neurodegenerative and cancer predisposition syndrome ataxia-telangiectasia. ATM protein kinase is activated by DNA damage and responds by phosphorylating downstream effectors involved in cell cycle arrest and DNA repair, such as p53, MDM2, CHEK2, BRCA1 and H2AX. ATM is probably a component of, or in close proximity to, the double-stranded DNA break-sensing machinery. We have observed purified human ATM protein, ATM-DNA and ATM-DNA-avidin bound complexes by single-particle electron microscopy and obtained three-dimensional reconstructions which show that ATM is composed of two main domains comprising a head and an arm. DNA binding to ATM induces a large conformational movement of the arm-like domain. Taken together, these three structures suggest that ATM is capable of interacting with DNA, using its arm to clamp around the double helix.
Llorca
O
O
The Institute of Cancer Research, Cancer Research UK, Center for Cell and Molecular Biology, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Rivera-Calzada
A
A
Grantham
J
J
Willison
K R
KR
D064007:Ataxia Telangiectasia Mutated Proteins; D001360:Avidin / Q000378:metabolism; D018797:Cell Cycle Proteins; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006801:Humans; D007091:Image Processing, Computer-Assisted; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D025521:Tumor Suppressor Proteins; D001360:Avidin; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases