A1 Refereed original research article in a scientific journal
Cooperative symmetric to asymmetric conformational transition of the apo-form of scavenger decapping enzyme revealed by simulations
Authors: Pentikainen U, Pentikainen OT, Mulholland AJ
Publisher: WILEY
Publication year: 2008
Journal: Proteins
Journal name in source: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Journal acronym: PROTEINS
Volume: 70
Issue: 2
First page : 498
Last page: 508
Number of pages: 11
ISSN: 0887-3585
DOI: https://doi.org/10.1002/prot.21540
Abstract
Decapping is a central step in eukaryotic mRNA turnover and in gene expression regulation. The human scavenger decapping enzyme, DcpS, catalyses cap hydrolysis following mRNA degradation. DcpS is a dimeric enzyme, with two active sites. Crystal structures suggest that DcpS must undergo significant conformational changes upon ligand binding, but the mechanism of this transition is unknown. Here, we report two long timescale (20 ns) molecular dynamics simulations of the apo-form of DcpS. The dimer is observed to undergo a strikingly cooperative motion, with one active site closing while the other opens. The amplitude of the conformational change is 6-21 angstrom and the apparent timescale is 4-13 ns. These findings indicate that the crystallographically observed symmetric conformation of apo-form of DcpS is only a minor conformation in solution. The simulations also show that active sites are structurally connected via the domain-swapped dimer structure of the N-terminal domain, even in the absence of a bound ligand. These findings suggest a functional reason for the enzyme existing as a dimer, and may be widely relevant, also for other dimeric proteins.
Decapping is a central step in eukaryotic mRNA turnover and in gene expression regulation. The human scavenger decapping enzyme, DcpS, catalyses cap hydrolysis following mRNA degradation. DcpS is a dimeric enzyme, with two active sites. Crystal structures suggest that DcpS must undergo significant conformational changes upon ligand binding, but the mechanism of this transition is unknown. Here, we report two long timescale (20 ns) molecular dynamics simulations of the apo-form of DcpS. The dimer is observed to undergo a strikingly cooperative motion, with one active site closing while the other opens. The amplitude of the conformational change is 6-21 angstrom and the apparent timescale is 4-13 ns. These findings indicate that the crystallographically observed symmetric conformation of apo-form of DcpS is only a minor conformation in solution. The simulations also show that active sites are structurally connected via the domain-swapped dimer structure of the N-terminal domain, even in the absence of a bound ligand. These findings suggest a functional reason for the enzyme existing as a dimer, and may be widely relevant, also for other dimeric proteins.
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