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From unwinding to clamping — the DEAD box RNA helicase family

Nature Reviews Molecular Cell Biology volume 12, pages 505–516 (2011)Cite this article

Subjects

Key Points

  • RNA helicases of the DEAD box family are important players in RNA metabolism in most living organisms. Despite high conservation between DEAD box proteins, they participate in many different processes.

  • Recent structural and functional analyses have changed our perception of these fascinating enzymes. They clamp the RNA substrate in an ATP-dependent manner, which can lead to the formation of an RNA-binding complex or to local unwinding of double-stranded RNA. Whereas ATP-binding is necessary and sufficient for RNA binding or unwinding, ATP hydrolysis is required for the release and recycling of the enzyme.

  • The binding to the RNA substrate, or the unwinding of a duplex RNA and the hydrolysis of ATP and release of phosphate, must be tightly regulated by other proteins and small molecules. Therefore, DEAD box RNA helicases act in complexes that are sometimes very large.

  • Three processes that beautifully exemplify these different concepts are the formation of the exon junction complex, the export of mRNA and translation initiation.

  • In the exon junction complex, eukaryotic initiation factor 4AIII (eIF4AIII) is bound to the mRNA and the hydrolysis of ATP and release of phosphate are controlled by partner proteins.

  • The export of mRNA through the nuclear complex involves many proteins. This process is assisted by DEAD box protein 5 (Dbp5) in yeast (DDX19 and DDX25 in vertebrates), which is required for the recycling of export factors and the release of the mRNA into the cytoplasm. Its activity is controlled by nuclear pore complex proteins and the small metabolite inositol hexakisphosphate.

  • eIF4A, which was the first DEAD box protein to be characterized, is required for translation initiation. Its activity is stimulated by the interaction with eIF4G, which is a large scaffolding protein of the cap-binding complex, and inhibited by the tumour suppressor protein programmed cell death 4 (PDCD4), the small RNA BC1 or the small natural products pateamine A or hippuristanol.

Abstract

RNA helicases of the DEAD box family are present in all eukaryotic cells and in many bacteria and Archaea. These highly conserved enzymes are required for RNA metabolism from transcription to degradation and are therefore important players in gene expression. DEAD box proteins use ATP to unwind short duplex RNA in an unusual fashion and remodel RNA–protein complexes, but they can also function as ATP-dependent RNA clamps to provide nucleation centres that establish larger RNA–protein complexes. Structural, mechanistic and molecular biological studies have started to reveal how these conserved proteins can perform such diverse functions and how accessory proteins have a central role in their regulation.

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Figure 1: Cellular processes involving DEAD box proteins.
Figure 2: Structure of the DEAD box helicase core and substrate interactions.
Figure 3: eIF4AIII clamps the EJC to the mRNA.
Figure 4: Regulation of eIF4A during translation initiation.
Figure 5: Dbp5 control of mRNA export.

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Acknowledgements

Work in the authors's laboratories is supported by the Swiss National Science Foundation and the Canton of Geneva (P.L.) and by the US National Institutes of Health (RO1GM006770) and the Burroughs Wellcome Fund (E.J.). The authors acknowledge the comments by the referees and the many generous and stimulating interactions in the DEAD box RNA helicase field. The authors apologize to all colleagues whose important contributions could not be highlighted or discussed here.

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Authors and Affiliations

  1. Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1, rue Michel Servet, Genève 4, 1211, Switzerland

    Patrick Linder

  2. Center for RNA Molecular Biology and Department of Biochemistry, Case Western Reserve University, Wood Building 137, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Eckhard Jankowsky

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Correspondence to Patrick Linder or Eckhard Jankowsky.

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DATABASES

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Glossary

Spliceosome

A large, dynamic complex that is composed of RNA and proteins and is involved in excising introns and joining the exons of pre-mRNA.

Small nuclear RNA

(snRNA). RNA molecules that serve as guides during pre-mRNA processing.

Small nucleolar RNA

(snoRNA). RNA molecules that serve as guides during pre-ribosomal RNA modification.

Mitochondrial RNA editing

Guide RNA-assisted insertion and modification of the sequence of mitochondrial mRNA in trypanosomes.

Transition state analogue

A compound that mimics the structure of the transition state, which is the state with the highest energy along the reaction coordinate.

ATP ground state

In helicases, this typically corresponds to the reaction state when ATP is bound by the enzyme but is not yet hydrolysed.

Nonsense-mediated RNA decay

(NMD). A process by which mRNA molecules that contain a stop codon within the open reading frame are subjected to rapid degradation to avoid synthesis of deleterious truncated proteins.

Nuclear speckles

Subnuclear structures that are enriched with pre-mRNA and many different proteins that are involved in splicing.

Next-generation sequencing

High-throughput sequencing technologies in which millions of (usually short) pieces of sequence are produced in parallel.

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Linder, P., Jankowsky, E. From unwinding to clamping — the DEAD box RNA helicase family. Nat Rev Mol Cell Biol 12, 505–516 (2011). https://doi.org/10.1038/nrm3154

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