Dynamics and Conformational Changes in Human NEIL2 DNA Glycosylase Analyzed by Hydrogen/Deuterium Exchange Mass Spectrometry

Polina V. Zhdanova, Alexander A. Ishchenko, Alexander A. Chernonosov, Dmitry O. Zharkov, Vladimir V. Koval

Результат исследования: Научные публикации в периодических изданияхстатьярецензирование

Аннотация

Base excision DNA repair (BER) is necessary for removal of damaged nucleobases from the genome and their replacement with normal nucleobases. BER is initiated by DNA glycosylases, the enzymes that cleave the N-glycosidic bonds of damaged deoxynucleotides. Human endonuclease VIII-like protein 2 (hNEIL2), belonging to the helix–two-turn–helix structural superfamily of DNA glycosylases, is an enzyme uniquely specific for oxidized pyrimidines in non-canonical DNA substrates such as bubbles and loops. The structure of hNEIL2 has not been solved; its closest homologs with known structures are NEIL2 from opossum and from giant mimivirus. Here we analyze the conformational dynamics of free hNEIL2 using a combination of hydrogen/deuterium exchange mass spectrometry, homology modeling and molecular dynamics simulations. We show that a prominent feature of vertebrate NEIL2 – a large insert in its N-terminal domain absent from other DNA glycosylases – is unstructured in solution. It was suggested that helix–two-turn–helix DNA glycosylases undergo open–close transition upon DNA binding, with the large movement of their N- and C-terminal domains, but the open conformation has been elusive to capture. Our data point to the open conformation as favorable for free hNEIL2 in solution. Overall, our results are consistent with the view of hNEIL2 as a conformationally flexible protein, which may be due to its participation in the repair of non-canonical DNA structures and/or to the involvement in functional and regulatory protein–protein interactions.

Язык оригиналаанглийский
Номер статьи167334
ЖурналJournal of Molecular Biology
Том434
Номер выпуска2
DOI
СостояниеОпубликовано - 30 янв. 2022

Предметные области OECD FOS+WOS

  • 1.06 БИОЛОГИЧЕСКИЕ НАУКИ
  • 1.06.CQ БИОХИМИЯ И МОЛЕКУЛЯРНАЯ БИОЛОГИЯ

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