Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha
- Helmholtz Zentrum München - German research center for environmental health, Germany
- Emory University, United States
- Technische Universität München, Germany
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.
Article and author information
Author details
Reviewing Editor
- Karsten Weis, ETH Zürich, Switzerland
Version history
- Received: September 3, 2015
- Accepted: January 7, 2016
- Accepted Manuscript published: January 8, 2016 (version 1)
- Accepted Manuscript updated: January 12, 2016 (version 2)
- Version of Record published: February 11, 2016 (version 3)
Copyright
© 2016, Weber et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha
eLife 5:e11297.
https://doi.org/10.7554/eLife.11297
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