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Proske, M. ; Janowski, R. ; Bacher, S. ; Kang, H.-S. ; Monecke, T.* ; Koehler, T.* ; Hutten, S.* ; Tretter, J. ; Crois, A.* ; Molitor, L. ; Varela-Rial, A.* ; Fino, R.* ; Donati, E.* ; De Fabritiis, G.* ; Dormann, D.* ; Sattler, M. ; Niessing, D.

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

eLife 13:27 (2024)
Postprint DOI PMC
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Pura ; Pura Syndrome ; Rna Binding ; X-ray Crystallography ; Cell Biology ; Human ; Molecular Biophysics ; Protein Folding Stability ; Structural Biology; Single-stranded-dna; Basic-protein Gene; Postnatal Brain-development; Rna-binding Protein; Nuclear Import; Ggggcc Repeat; Alpha; Transcription; Dynamics; Reveals
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Journal eLife
Quellenangaben Volume: 13, Issue: , Pages: , Article Number: 27 Supplement: ,
Publisher eLife Sciences Publications
Publishing Place Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants PURA Syndrome Foundation
PURA Foundation Australia
Deutsche Forschungsgemeinschaft