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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
Open Access Hybrid
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Zeitschrift eLife
Quellenangaben Band: 13, Heft: , Seiten: , Artikelnummer: 27 Supplement: ,
Verlag eLife Sciences Publications
Verlagsort Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503091-001
G-503000-001
Förderungen PURA Syndrome Foundation
PURA Foundation Australia
Deutsche Forschungsgemeinschaft
DOI 10.7554/eLife.93561
WOS ID 001207926600001
PubMed ID 38655849
Erfassungsdatum 2024-06-19
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