The Lin28 cold-shock domain remodels pre-let-7 microRNA.

Nucleic Acids Research
Florian MayrUdo Heinemann

Abstract

The RNA-binding protein Lin28 regulates the processing of a developmentally important group of microRNAs, the let-7 family. Lin28 blocks the biogenesis of let-7 in embryonic stem cells and thereby prevents differentiation. It was shown that both RNA-binding domains (RBDs) of this protein, the cold-shock domain (CSD) and the zinc-knuckle domain (ZKD) are indispensable for pri- or pre-let-7 binding and blocking its maturation. Here, we systematically examined the nucleic acid-binding preferences of the Lin28 RBDs and determined the crystal structure of the Lin28 CSD in the absence and presence of nucleic acids. Both RNA-binding domains bind to single-stranded nucleic acids with the ZKD mediating specific binding to a conserved GGAG motif and the CSD showing only limited sequence specificity. However, only the isolated Lin28 CSD, but not the ZKD, can bind with a reasonable affinity to pre-let-7 and thus is able to remodel the terminal loop of pre-let-7 including the Dicer cleavage site. Further mutagenesis studies reveal that the Lin28 CSD induces a conformational change in the terminal loop of pre-let-7 and thereby facilitates a subsequent specific binding of the Lin28 ZKD to the conserved GGAG motif.

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Citations

Apr 30, 2013·Nature Structural & Molecular Biology·David W TaylorHong-Wei Wang
Aug 14, 2013·International Journal of Molecular Sciences·Florian Mayr, Udo Heinemann
Jan 24, 2014·Nucleic Acids Research·Alexandre DesjardinsPascale Legault
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Methods Mentioned

BETA
size-exclusion chromatography
gel filtration
X-ray
isothermal titration calorimetry
electrophoretic mobility shift assay
PCR
in vitro transcription
electrophoretic mobility shift
NMR
fluorescence titration

Software Mentioned

Mfold
GraphPad Prism
HKL2000
ARP
wARP
COOT
GraphPad
REFMAC
iMOSFLM
ImageQuant

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