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TitleNear-Complete Structure and Model of Tel1ATM from Chaetomium thermophilum Reveals a Robust Autoinhibited ATP State.
Journal, issue, pagesStructure, Vol. 28, Issue 1, Page 83-95.e5, Year 2020
Publish dateJan 7, 2020
AuthorsMarijke Jansma / Christian Linke-Winnebeck / Sebastian Eustermann / Katja Lammens / Dirk Kostrewa / Kristina Stakyte / Claudia Litz / Brigitte Kessler / Karl-Peter Hopfner /
PubMed AbstractTel1 (ATM in humans) is a large kinase that resides in the cell in an autoinhibited dimeric state and upon activation orchestrates the cellular response to DNA damage. We report the structure of an ...Tel1 (ATM in humans) is a large kinase that resides in the cell in an autoinhibited dimeric state and upon activation orchestrates the cellular response to DNA damage. We report the structure of an endogenous Tel1 dimer from Chaetomium thermophilum. Major parts are at 2.8 Å resolution, including the kinase active site with ATPγS bound, and two different N-terminal solenoid conformations are at 3.4 Å and 3.6 Å, providing a side-chain model for 90% of the Tel1 polypeptide. We show that the N-terminal solenoid has DNA binding activity, but that its movements are not coupled to kinase activation. Although ATPγS and catalytic residues are poised for catalysis, the kinase resides in an autoinhibited state. The PIKK regulatory domain acts as a pseudo-substrate, blocking direct access to the site of catalysis. The structure allows mapping of human cancer mutations and defines mechanisms of autoinhibition at near-atomic resolution.
External linksStructure / PubMed:31740028
MethodsEM (single particle)
Resolution2.8 - 3.7 Å
Structure data

10231

6sky

EMDB-10231, PDB-6sky:
FAT and kinase domain of CtTel1
Method: EM (single particle) / Resolution: 2.8 Å

10232

6skz

EMDB-10232, PDB-6skz:
Structure of the closed conformation of CtTel1
Method: EM (single particle) / Resolution: 3.4 Å

10233

6sl0

EMDB-10233, PDB-6sl0:
Complete CtTel1 dimer with C2 symmetry
Method: EM (single particle) / Resolution: 3.7 Å

10234

6sl1

EMDB-10234, PDB-6sl1:
Structure of the open conformation of CtTel1
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

Source
  • Chaetomium thermophilum var. thermophilum DSM 1495 (fungus)
  • chaetomium thermophilum (strain dsm 1495 / cbs 144.50 / imi 039719) (fungus)
KeywordsTRANSFERASE / Kinase / alpha solenoid / PIKK / nucleus / tranferase / dimer / DNA damage signaling / ATM

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