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Nat Struct Mol Biol. 2016 Nov;23(11):987-994. doi: 10.1038/nsmb.3301. Epub 2016 Oct 3.

Structural basis of mRNA-cap recognition by Dcp1-Dcp2.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
2
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
3
Centre of New Technologies, University of Warsaw, Warsaw, Poland.

Abstract

Removal of the 5' cap on mRNA by the decapping enzyme Dcp2 is a critical step in 5'-to-3' mRNA decay. Understanding the structural basis of Dcp2 activity has been a challenge because Dcp2 is dynamic and has weak affinity for the cap substrate. Here we present a 2.6-Å-resolution crystal structure of a heterotrimer of fission yeast Dcp2, its essential activator Dcp1, and the human NMD cofactor PNRC2, in complex with a tight-binding cap analog. Cap binding is accompanied by a conformational change in Dcp2, thereby forming a composite nucleotide-binding site comprising conserved residues in the catalytic and regulatory domains. Kinetic analysis of PNRC2 revealed that a conserved short linear motif enhances both substrate affinity and the catalytic step of decapping. These findings explain why Dcp2 requires a conformational change for efficient catalysis and reveals that coactivators promote RNA binding and the catalytic step of decapping, possibly through different conformational states.

PMID:
27694842
PMCID:
PMC5113729
DOI:
10.1038/nsmb.3301
[Indexed for MEDLINE]
Free PMC Article

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