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Weber, J. ; Bao, H.* ; Hartlmüller, C.* ; Wang, Z.* ; Windhager, A. ; Janowski, R. ; Madl, T. ; Jin, P.* ; Niessing, D.

Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha.

eLife 5:e11297 (2016)

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The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA-localization. Pur-alpha deficient mice die after birth with pleiotropic neuronal defects. Here we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specific recognition and offers a molecular explanation for the effect of point mutations in the 5q31.3 microdeletion syndrome. Consistent with the crystal structure, biochemical and NMR data indicate that Pur-alpha binds DNA and RNA in the same way, suggesting binding modes for tri- and hexanucleotide repeat RNAs in two neurodegenerative RNAopathies. Additionally, structure-based in vitro experiments resolved the molecular mechanism of Pur-alpha's unwindase activity. Complementing in vivo analyses in Drosophila demonstrated the importance of a highly conserved phenylalanine for Pur-alpha's unwinding and neuroprotective function. By uncovering the molecular mechanisms of nucleic-acid binding, this study contributes to understanding the cellular role of Pur-alpha and its implications in neurodegenerative diseases.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords D. Melanogaster ; E. Coli ; Biochemistry ; Biophysics ; Structural Biology; Amyotrophic-lateral-sclerosis; Postnatal Brain-development; Dna-binding Protein; Fragile-x; Repeat Expansion; Ggggcc Repeat; Nucleocytoplasmic Transport; Mediated Neurodegeneration; Frontotemporal Dementia; Drosophila Model

ISSN (print) / ISBN 2050-084X

e-ISSN 2050-084X

Journal eLife

Quellenangaben Volume: 5, Article Number: e11297

Publisher eLife Sciences Publications

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)