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Prolyl Isomerization-Mediated Conformational Changes Define ATR Subcellular Compartment-Specific Functions.

Himadri Biswas1, Shu-Jun Zhao2,3, Yetunde Makinwa1

  • 1Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States.

Frontiers in Cell and Developmental Biology
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PubMed
Summary

The ATR protein exists in two forms, cis-ATR and trans-ATR, which determine its location and function in DNA damage response and cell survival. Isomerization at the Pin1 motif drives these structural and functional changes.

Keywords:
ATRBH3-like domainUV irradiationantiapoptosiscis/trans prolyl isomerizationmass spectrometric protein footprintingmitochondrial ATR-tBid interactionstructure-function of ATR

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • ATR (Ataxia Telangiectasia and Rad3-related) is a PI3K-like kinase crucial for DNA damage and replication stress responses.
  • ATR functions in the nucleus as a checkpoint kinase and in the mitochondria for anti-apoptotic roles.
  • Two prolyl isomeric forms, trans-ATR (nuclear) and cis-ATR (cytoplasmic/mitochondrial), mediate these distinct functions via isomerization at the Pin1 Ser428-Pro429 motif.

Purpose of the Study:

  • To elucidate the structural basis for the subcellular location-specific functions of human ATR.
  • To understand how ATR isomerization influences its conformation, localization, and interactions.

Main Methods:

  • Mass spectrometry-based footprinting to compare surface accessibility of lysine residues in cis- and trans-ATR.
  • Complementary biochemical assays to assess protein-protein interactions.
  • Molecular modeling and dynamics simulations of the ATR Ser428-Pro429 motif and BH3 domain.

Main Results:

  • Identified conformational changes in cis-ATR, specifically increased accessibility of K459 and K469 in the BH3-like domain, absent in trans-ATR.
  • Demonstrated that cis-ATR binds to tBid via its accessible BH3 domain, while trans-ATR cannot.
  • Showed that both cis- and trans-ATR form homodimers, with trans-ATR forming larger complexes with ATRIP in the nucleus after UV irradiation.
  • Molecular dynamics simulations indicated the cis conformation is energetically more favorable.

Conclusions:

  • ATR isomerization at the Pin1 motif induces significant structural changes, altering its subcellular localization and compartment-specific functions.
  • These conformational shifts are critical for ATR's role in DNA damage response and cell survival pathways.
  • The study provides a structural framework for understanding ATR's dual role in nuclear checkpoints and mitochondrial anti-apoptosis.