Analysis of decapping scavenger cap complex using modified cap analogs reveals molecular determinants for efficient cap binding

FEBS J. 2013 Dec;280(24):6508-27. doi: 10.1111/febs.12553. Epub 2013 Oct 23.


Decapping scavenger (DcpS) assists in precluding inhibition of cap-binding proteins by hydrolyzing cap species remaining after mRNA 3'→5' degradation. Its significance was reported in splicing, translation initiation and microRNA turnover. Here we examine the structure and binding mode of DcpS from Caenorhabditis elegans (CeDcpS) using a large collection of chemically modified methylenebis(phosphonate), imidodiphosphate and phosphorothioate cap analogs. We determine that CeDcpS is a homodimer and propose high accuracy structural models of apo- and m(7) GpppG-bound forms. The analysis of CeDcpS regioselectivity uncovers that the only site of hydrolysis is located between the β and γ phosphates. Structure-affinity relationship studies of cap analogs for CeDcpS reveal molecular determinants for efficient cap binding: a strong dependence on the type of substituents in the phosphate chain, and reduced binding affinity for either methylated hydroxyl groups of m(7) Guo or an extended triphosphate chain. Docking analysis of cap analogs in the CeDcpS active site explains how both phosphate chain mobility and the orientation in the cap-binding pocket depend on the number of phosphate groups, the substituent type and the presence of the second nucleoside. Finally, the comparison of CeDcpS with its well known human homolog provides general insights into DcpS-cap interactions.

Keywords: cap analogs; fluorescence spectroscopy; mRNA degradation; molecular docking; scavenger decapping enzymes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Catalytic Domain
  • Chromatography, Gel
  • Chromatography, High Pressure Liquid
  • Gene Expression Regulation*
  • Humans
  • Hydrolysis
  • Models, Molecular
  • Molecular Sequence Data
  • Pyrophosphatases / chemistry
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism*
  • RNA Cap Analogs / chemistry
  • RNA Cap Analogs / genetics
  • RNA Cap Analogs / metabolism*
  • RNA Caps / chemistry
  • RNA Caps / genetics
  • RNA Caps / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*


  • Caenorhabditis elegans Proteins
  • RNA Cap Analogs
  • RNA Caps
  • RNA, Messenger
  • Pyrophosphatases
  • dcs-1 protein, C elegans