eLife (Apr 2024)

PURA syndrome-causing mutations impair PUR-domain integrity and affect P-body association

  • Marcel Proske,
  • Robert Janowski,
  • Sabrina Bacher,
  • Hyun-Seo Kang,
  • Thomas Monecke,
  • Tony Koehler,
  • Saskia Hutten,
  • Jana Tretter,
  • Anna Crois,
  • Lena Molitor,
  • Alejandro Varela-Rial,
  • Roberto Fino,
  • Elisa Donati,
  • Gianni De Fabritiis,
  • Dorothee Dormann,
  • Michael Sattler,
  • Dierk Niessing

DOI
https://doi.org/10.7554/eLife.93561
Journal volume & issue
Vol. 13

Abstract

Read online

Mutations in the human PURA gene cause the neurodevelopmental PURA syndrome. In contrast to several other monogenetic disorders, almost all reported mutations in this nucleic acid-binding protein result in the full disease penetrance. In this study, we observed that patient mutations across PURA impair its previously reported co-localization with processing bodies. These mutations either destroyed the folding integrity, RNA binding, or dimerization of PURA. We also solved the crystal structures of the N- and C-terminal PUR domains of human PURA and combined them with molecular dynamics simulations and nuclear magnetic resonance measurements. The observed unusually high dynamics and structural promiscuity of PURA indicated that this protein is particularly susceptible to mutations impairing its structural integrity. It offers an explanation why even conservative mutations across PURA result in the full penetrance of symptoms in patients with PURA syndrome.

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