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The double-stranded-RNA-binding motif: interference and much more

Nature Reviews Molecular Cell Biology volume 5, pages 1013–1023 (2004)Cite this article

Key Points

  • Many proteins that interact with highly structured RNA contain double-stranded RNA-binding motifs (dsRBMs). Well-known examples include the nucleases RNase III and Dicer, the protein kinase PKR, RNA deaminases (ADARs) and Staufen, a protein that is responsible for mRNA localization.

  • The dsRBM adopts an α–β–β–β–α topology structure with conserved residues at critical locations, particularly in the C-terminal third of the motif. Three regions of the dsRBM are involved in contacting A-form RNA along one face of the helix without wrapping around it.

  • The dsRBM interacts with the RNA duplex without obvious sequence specificity. However, several dsRBM proteins show a high degree of substrate specificity that can be of great biological significance.

  • The dsRBM is associated with ∼20 other protein domains in proteins from all eukaryotes, most eubacteria, several viruses and one Archaeon. Evolutionarily advanced organisms have a greater number of dsRBM proteins than lower species.

  • When there are several dsRBMs in a single protein, cooperation between them can achieve a higher affinity to RNAs, and some dsRBMs can adopt activities other than dsRNA binding, for example, protein–protein interactions.

  • dsRBM proteins are involved in a myriad of cellular functions, from RNA interference to antiviral mechanisms and other types of post-transcriptional gene regulation. Duplexed RNAs can be substrates, modulators or cargos for dsRBM proteins. There are extensive interactions between dsRBM proteins. Some are involved in the same cellular pathway, such as the interferon response and RNA interference, whereas some seem to modulate the functions of others.

Abstract

RNA duplexes have been catapulted into the spotlight by the discovery of RNA interference and related phenomena. But double-stranded and highly structured RNAs have long been recognized as key players in cell processes ranging from RNA maturation and localization to the antiviral response in higher organisms. Penetrating insights into the metabolism and functions of such RNAs have come from the identification and study of proteins that contain the double-stranded-RNA-binding motif.

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Figure 1: Secondary and tertiary structural elements in RNA.
Figure 2: Two views of the dsRBM structure.
Figure 3: Sequence logo of the dsRBM.
Figure 4: Domain structures of dsRBM proteins.

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Acknowledgements

We thank B. Golden at Purdue University for assistance with figure 2 and H. Zhang at New Jersey Medical School for assistance with figure 4. Support from the following funding agencies is acknowledged: from the National Institutes of Health to P.C.B. and M.B.M. and from the American Cancer Society to A.D.P.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, PO Box 1709, Newark, 07101-1709, New Jersey, USA

    Bin Tian & Michael B. Mathews

  2. Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, 16802, Pennsylvania, USA

    Philip C. Bevilacqua

  3. Division of Mathematics and Natural Sciences, Altoona College, The Pennsylvania State University, 3000 Ivyside Park, Altoona, 16601, Pennsylvania, USA

    Amy Diegelman-Parente

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  1. Bin Tian
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  2. Philip C. Bevilacqua
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Correspondence to Michael B. Mathews.

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DATABASES

Flybase

Drosha

R2D2

Staufen

Interpro

dsRBD

RNB

SwissProt

ADAR1

ADAR2

Dicer

MRPL44

NF90

NRF

PACT

PKR

TRBP

Xlrbpa

FURTHER INFORMATION

Michael Mathews' laboratory

Bin Tian's laboratory

Glossary

RNA-RECOGNITION MOTIF

(RRM). This motif is among the most common in eukaryotic proteins. It usually comprises 80–90 amino acids, forming a β–α–β–β–α–β structure. Many proteins that contain RRMs bind RNA in a sequence-specific manner.

RNASE III

An endoribonuclease that cleaves RNA substrates containing regular double-helical or stem-loop structures.

APTAMER

An RNA, either engineered or natural, that forms a precise three-dimensional structure and selectively binds a target molecule, for example a dsRBM-containing protein.

3′ UNTRANSLATED REGION

(3′ UTR). This is the sequence of a messenger RNA that is located downstream of the stop codon.

HELICAL CHIMAERA

A helix in which one of the strands has a mixture of ribose and deoxyribose nucleotides.

ANTIDETERMINANTS

Sequences that block the binding of a protein to an otherwise suitable site, first defined in tRNAs and later in RNase-III substrates.

ADENOSINE DEAMINASE

An enzyme that catalyses adenosine-to-inosine conversion in an RNA substrate, a process also known as RNA editing.

Z-α-DOMAIN

A protein domain that binds left-handed Z-form DNA, which is believed to occur transiently in the cell during gene transcription.

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Tian, B., Bevilacqua, P., Diegelman-Parente, A. et al. The double-stranded-RNA-binding motif: interference and much more. Nat Rev Mol Cell Biol 5, 1013–1023 (2004). https://doi.org/10.1038/nrm1528

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