The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans, but the mechanism of its activation remains unclear. ATR acts together with its partner ATRIP. Using cryo-electron microscopy, we determined the structure of intact Mec1-Ddc2 (the yeast homolog of ATR-ATRIP), which is poised for catalysis, at a resolution of 3.9 angstroms. Mec1-Ddc2 forms a dimer of heterodimers through the PRD and FAT domains of Mec1 and the coiled-coil domain of Ddc2. The PRD and Bridge domains in Mec1 constitute critical regulatory sites. The activation loop of Mec1 is inhibited by the PRD, revealing an allosteric mechanism of kinase activation. Our study clarifies the architecture of ATR-ATRIP and provides a structural framework for the understanding of ATR regulation.
ATM/Tel1 is an apical kinase that orchestrates the multifaceted DNA damage response. Mutations of ATM/Tel1 are associated with ataxia telangiectasia syndrome. Here, we report cryo-EM structures of symmetric dimer (4.1 Å) and asymmetric dimer (4.3 Å) of Saccharomyces cerevisiae Tel1. In the symmetric state, the side chains in Tel1 C-terminus (residues 1129–2787) are discernible and an atomic model is built. The substrate binding groove is completely embedded in the symmetric dimer by the intramolecular PRD and intermolecular LID domains. Point mutations in these domains sensitize the S. cerevisiae cells to DNA damage agents and hinder Tel1 activation due to reduced binding affinity for its activator Xrs2/Nbs1. In the asymmetric state, one monomer becomes more compact in two ways: the kinase N-lobe moves down and the Spiral of α-solenoid moves upwards, which resemble the conformational changes observed in active mTOR. The accessibility of the activation loop correlates with the synergistic conformational disorders in the TRD1-TRD2 linker, FATC and PRD domains, where critical post-translational modifications and activating mutations are coincidently condensed. This study reveals a tunable allosteric network in ATM/Tel1, which is important for substrate recognition, recruitment and efficient phosphorylation.
The coupling and evolution of two-mode ablative Rayleigh-Taylor instability (ARTI) in two-dimensional geometry are studied via numerical simulations. We focus primarily on two scenarios: Coupling and bubble competition of a long and a short wavelength mode and of two short-wavelength modes. It is found that the long-wavelength modes tend to dominate in the nonlinear phase of the long-short coupling cases. The presence of the short-wavelength mode in the long-short cases enhances the total ARTI bubble vertex velocity. However, due to the formation of enclosed bubbles, this enhancement does not increase monotonically with the initial short-wavelength amplitude. Coupling of two short-wavelength modes forms a long-wavelength component which grows faster than each individual short-wavelength mode.
No abstract
Self-generated magnetic fields in single-mode ablative Rayleigh–Taylor instability (ARTI) relevant to the acceleration phase of inertial confinement fusion (ICF) implosions are studied via two dimensional simulations. In ARTI, [Formula: see text] T magnetic fields can be generated via the Biermann battery source without considering the Nernst effect. The Nernst effect significantly compresses the magnetic field against the electron temperature gradient and amplifies the peak value by more than three times. A scaling law for the magnetic flux is obtained, and it well predicts the evolution of the magnetic field from linear to deeply nonlinear phases of ARTI. The self-generated magnetic field reduces the ablation near the spike and reduces the width of bubbles by magnetizing the electron heat flows, which results in higher magnitude vorticity inside the bubble and enhances the nonlinear ARTI bubble penetration velocity for short-wavelength modes. The bubble velocity boosting due to self-generated magnetic field indicates the larger impact of the short-wavelength ARTI modes on ICF implosion performance than previously expected.
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