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

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.

journal_name

Elife

journal_title

eLife

authors

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

doi

10.7554/eLife.11297

subject

Has Abstract

pub_date

2016-01-08 00:00:00

issn

2050-084X

journal_volume

5

pub_type

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