Structural highlights
Function
[G0S4S9_CHATD] Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates histone H2A to form H2AS128ph (gamma-H2A) at sites of DNA damage, involved in the regulation of DNA damage response mechanism. Required for the control of telomere length and genome stability.[RuleBase:RU365027]
Publication Abstract from PubMed
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 A resolution, including the kinase active site with ATPgammaS bound, and two different N-terminal solenoid conformations are at 3.4 A and 3.6 A, 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 ATPgammaS 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.
Near-Complete Structure and Model of Tel1ATM from Chaetomium thermophilum Reveals a Robust Autoinhibited ATP State.,Jansma M, Linke-Winnebeck C, Eustermann S, Lammens K, Kostrewa D, Stakyte K, Litz C, Kessler B, Hopfner KP Structure. 2019 Nov 6. pii: S0969-2126(19)30354-5. doi:, 10.1016/j.str.2019.10.013. PMID:31740028[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jansma M, Linke-Winnebeck C, Eustermann S, Lammens K, Kostrewa D, Stakyte K, Litz C, Kessler B, Hopfner KP. Near-Complete Structure and Model of Tel1ATM from Chaetomium thermophilum Reveals a Robust Autoinhibited ATP State. Structure. 2019 Nov 6. pii: S0969-2126(19)30354-5. doi:, 10.1016/j.str.2019.10.013. PMID:31740028 doi:http://dx.doi.org/10.1016/j.str.2019.10.013
