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Author Notes:

For correspondence: dierk.niessing@med.uni-muenchen.de

JW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

HB, CH, ZW, Acquisition of data, Analysis and interpretation of data, Contributed unpublished essential data or reagents

AW, Conception and design, Acquisition of data, Analysis and interpretation of data, Contributed unpublished essential data or reagents

RJ, TM, PJ, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

DN, Conception and design, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

We thank Marietta Truger and Stephane Roche for support during structure determination.

Competing interests: The authors declare that no competing interests exist.

Subjects:

Research Funding:

Deutsche Forschungsgemeinschaft

Bayerisches Staatsministerium fur Bildung und Kultus, Wissenschaft und Kunst

For full funding information, see page 19.

Keywords:

  • 5q31.3 microdeletion syndrome
  • d. melanogaster
  • e. coli
  • ALS
  • DNA unwinding
  • DNA-/RNA-protein interaction
  • FXTAS
  • X-ray crystallography
  • biochemistry
  • biophysics
  • structural biology

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

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Journal Title:

eLife

Volume:

Volume 5

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 2016, Weber et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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