Control of mRNA decapping by Dcp2: An open and shut case?

Abstract

mRNA decapping by Dcp2 is a critical step in several major eukaryotic mRNA decay pathways. Dcp2 forms the catalytic core of a mRNP that is configured for processing diverse substrates by pathway-specific activators. Here we elaborate a model of catalysis by Dcp2 which posits that activity is controlled by a conformational equilibrium between an open, inactive and closed, active form of the enzyme. Structural studies on yeast Dcp2 indicate that the general activator Dcp1 and substrate promote the closed form of the enzyme. Kinetic studies indicate the catalytic step of decapping is rate-limiting and accelerated by Dcp1. We propose that regulation of conformational transitions in Dcp2 during a rate-limiting step after assembly of the decapping mRNP provides a checkpoint for determining if an mRNA is degraded or recycled to translation.

Figure 1

The open-closed transition of Dcp2. Dcp1 is in yellow, the N-terminal domain of Dcp2 in blue, and the Nudix domain in green. The catalytic Nudix helix is highlighted in red and a substrate-mimic ATP molecule is in gray. Figure generated from PDB coordinates 2qkm .

Figure 2

A model of decapping regulation by the open-closed transition of Dcp2. The measured catalytic rate corresponds to all steps after binding. Color code: yellow-- Dcp1; blue--Dcp2 N-terminal domain; green—Dcp2 catalytic domain; magenta—capped RNA