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Nat Struct Mol Biol. 2016 Jan;23(1):16-23. doi: 10.1038/nsmb.3140. Epub 2015 Dec 7.

Recognition of distinct RNA motifs by the clustered CCCH zinc fingers of neuronal protein Unkempt.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
2
Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
3
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
4
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
#
Contributed equally

Abstract

Unkempt is an evolutionarily conserved RNA-binding protein that regulates translation of its target genes and is required for the establishment of the early bipolar neuronal morphology. Here we determined the X-ray crystal structure of mouse Unkempt and show that its six CCCH zinc fingers (ZnFs) form two compact clusters, ZnF1-3 and ZnF4-6, that recognize distinct trinucleotide RNA substrates. Both ZnF clusters adopt a similar overall topology and use distinct recognition principles to target specific RNA sequences. Structure-guided point mutations reduce the RNA binding affinity of Unkempt both in vitro and in vivo, ablate Unkempt's translational control and impair the ability of Unkempt to induce a bipolar cellular morphology. Our study unravels a new mode of RNA sequence recognition by clusters of CCCH ZnFs that is critical for post-transcriptional control of neuronal morphology.

PMID:
26641712
PMCID:
PMC4703518
DOI:
10.1038/nsmb.3140
[Indexed for MEDLINE]
Free PMC Article

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