Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export - PubMed (original) (raw)

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Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export

Andrew W Folkmann et al. Nucleus. 2011 Nov-Dec.

Abstract

Gene expression is a stepwise process involving distinct cellular processes including transcription, mRNA (mRNA) processing, mRNA export, and translation. As mRNAs are being synthesized, proteins associate with the RNA to form messenger ribonucleoprotein particles (mRNPs). Previous studies have demonstrated that the RNA-binding protein composition of these mRNPs is dynamic, changing as the mRNP moves through the different steps of gene expression, and playing a critical role in these events. An important step during this maturation process occurs at the cytoplasmic face of the nuclear pore complex (NPC) where the export protein Gle1 bound to inositol hexakisphosphate (IP 6) spatially activates the ATP-hydrolysis and mRNP-remodeling activity of the DEAD-box protein Dbp5. Recent work from our laboratory and others has provided important insights into the function and regulation of Dbp5. These include a more detailed explanation of the mechanism of Dbp5 RNP remodeling, the role of Gle1-IP6 in stimulating Dbp5 ATPase activity, and the identification of a novel paradigm for regulation of Dbp5 by Nup159. Based on in vitro biochemical assays, X-ray crystallography, and corresponding in vivo phenotypes, we propose here an updated model of the Dbp5 cycle during mRNP export through the NPC. This takes into account all available data and provides a platform for future studies.

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Figures

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Figure 1. Structural organization of a DEAD box protein. (A) Topology model of the RecA-like helicase domains of a generic DEAD-box protein. The positions of the conserved sequence motifs within the labeled RecA helicase domains are indicated with Roman numerals. (B) Structure of human Dbp5 bound with ATP analog (black) [PDB 3GOH]. Highlighted conserved sequence motifs include those involved in nucleotide binding and hydrolysis (Green); RNA binding and ATP hydrolysis (Pink); RNA binding (Blue).

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Figure 3. Working model for Dbp5/Gle1-IP6/Nup159 mRNA export cycle. During export, the mRNP exits the NPC where it encounters both Gle1-IP6 and Dbp5 at the cytoplasmic fibrils (Steps 1–2). Gle1-IP6 binds Dbp5 and enhances ATP loading (Steps 3–4). The ATP/Dbp5/Gle1-IP6 complex then binds to the mRNP, which stimulates both the release of Gle1-IP6 and the ATP hydrolysis event (Step 5). The change from ATP to ADP triggers a conformational change that drives both the remodeling of the mRNP and release of the mRNA from Dbp5 (Step 6). Dbp5-ADP is then recycled by interaction with Nup159 to release ADP (Step 7), and positioning for binding to Gle1 to begin the cycle again. The released RNA-binding proteins bind to cytoplasmic karyopherins for import back into the nucleus (Step 8).

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Figure 2. Solvent electrostatics of S. cerevisiae and human Dbp5. Solvent-excluded surface views of (A) human Δ53dbp5-ANPNP-RNA protein [PDB 3G0H], (B) human Δ53Dbp5-ADP protein [PDB 3EWS], (C) yeast (S. cerevisiae) Δ90dbp5L327V-ADP·BeF3 protein [PDB 3PEW], and (D) yeast (S. cerevisiae) Δ90dbp5L327V-ADP-Δ243 gle1H337R_-_IP6 proteins [PDB 3RRN] are shown colored by solvent accessible electrostatics contoured at −7 (red) to +7 _k_T/e (blue). The electrostatic potential was mapped to a molecular surface calculated using UCSF Chimera with default settings, as indicated by the PDB coordinates in brackets above. RNA is shown in green.

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