From unwinding to clamping — the DEAD box RNA helicase family

Abstract

Nearly all aspects of RNA metabolism, from transcription and translation to mRNA decay, involve RNA helicases, which are enzymes that use ATP to bind or remodel RNA and RNA-protein complexes (ribonucleoprotein (RNP) complexes) 1 . RNA helicases are found in all three domains of life, and many viruses also encode one or more of these proteins 2,3 . Together with the structurally related DNA helicases that function in replication, recombination and repair, the RNA helicases are classified into superfamilies and families, based on sequence and structural features 3,4 . DEAD box proteins form the largest helicase family, with 37 members in humans and 26 in Saccharomyces cerevisiae 3 , and are characterized by the presence of an Asp-Glu-Ala-Asp (DEAD) motif.DEAD box helicases have central and, in many cases, essential physiological roles in cellular RNA metabolism 5 (FIG. 1). The proteins generally function as part of larger multicomponent assemblies, such as the spliceosom e or the eukaryotic translation initiation machinery 6 . Mutations and deregulation of several DEAD box proteins have been linked to disease states, including cancer 7 . Although all DEAD box proteins contain a structurally highly conserved core with conserved ATP-binding and RNA-binding sites, different proteins have been associated with diverse and seemingly unrelated functions, including the disassembly of RNPs, chaperoning during RNA folding and even stabil ization of protein complexes on RNA 5,6 . How these highly conserved proteins fulfil such an array of different functions has been a long-standing question.Research has now started to illuminate the molecular basis for this functional diversity. In this Review, we summarize how structural data, together with biochemical and biophysical studies, have revealed unexpected modes by which these proteins function. We also discuss how novel molecular and cell biological approaches have better defined the cellular roles of DEAD box helicases. We outline our current view on common structural and mechan istic themes that have emerged, and on physical models of how these 'unusual' RNA helicases work.Structures of DEAD box RNA helicases A number of structural studies have universally shown that members of the DEAD box family contain a highly conserved helicase core that harbours the binding sites for ATP and RNA 3,4,8 . The core is surrounded by variable auxiliary domains, which are thought to be critical for the diverse functions of these enzymes.Structure of the helicase core. DEAD box proteins belong to helicase superfamily 2 (SF2) 2 . Similarly to all SF2 helicases, DEAD box proteins are built around a highly conserved helicase core of two virtually identical domains that resemble the bacterial recombination protein recombinase A (RecA) 3,4,8 (FIG. 2a,b). Within this helicase core, at least 12 characteristic sequence motifs are located at conserved positions (FIG. 2a,b). Some of these motifs are conserved across the entire SF2 family, whereas others are found only in the DEAD box family 3 ....

DEAD-Box RNA Helicases in Gram-Positive RNA Decay

“…Proteins from the DEAD-box RNA helicase family represent the largest family of helicase proteins throughout eukaryotic and prokaryotic systems (Linder and Jankowsky, 2011;Tanner et al, 2003). DEAD-box proteins can be defined by the presence of 12 conserved motifs ( Jankowsky, 2011).…”

Myeloid neoplasms with germline DDX41 mutation

“…The family of DEAD-box helicases are key proteins in multiple diverse cellular pathways and processes [47]. In particular, DDX41 interacts with core splicing proteins.…”

Contribution of SNRNP200 sequence variations to retinitis pigmentosa

“…They consist of a helicase core containing 12 conserved motifs involved in ATP binding, RNA binding, and ATP hydrolysis. 23 They all possess an ATPase activity that is stimulated by RNA, giving rise to a broad range of biochemical effects in vitro. Thus, they can often unwind short RNA duplexes.…”

“…However, they also can displace RNA-bound proteins, accelerate RNA strand annealing or RNA folding, and act as RNA clamps to form stable ribonucleoprotein (RNP) complexes. 23 In yeast, the sec-63 domain is required to reconstitute post-translational translocation in protoliposomes. 24 Yeast BiP/Kar2p binds to a DnaJ domain of sec-63 and mediates the import of polypeptides into the endoplasmic reticulum (ER) lumen 25 and the export of misfolded proteins into the cytoplasm.…”

“…10 Genetically RP is a highly heterogeneous condition. More than 60 RP genes have been identified, while 23,36, and 3 genes were responsible for adRP, arRP, and xlRP, respectively (RetNet, the Retinal Information Network, University of Texas Houston Health Science Center, Houston, TX, accessed on 22 November 2012). Despite this large number of genes, the vast majority was mapped in populations other than Chinese.…”