RNA helicases — one fold for many functions

Jankowsky, Eckhard; Fairman, Margaret E.

doi:10.1016/j.sbi.2007.05.007

Cited by 236 publications

(281 citation statements)

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“…RNA unwinding measured in vitro with defined model substrates is considered an excellent proxy for the ATP-dependent binding and remodelling of more complex RNA and RNP structures that DEAD box proteins are thought to perform in the cell during processes such as ribosome biogenesis or pre-mRNA splicing 1,26 . DEAD box proteins are bona fide heli cases that use ATP to bind and unwind RNA duplexes 27 .…”

Section: Mitochondrial Rna Editingmentioning

confidence: 99%

“…Despite quantitative distinctions between differen t helicases, which may affect their specific biologica l functions, unwinding by local strand separation is exceptionally well suited for the RNA or RNP remodelling that many DEAD box proteins are thought to conduct in the cell 26 . Their highly localized unwindin g mode prevents large-scale unravelling of carefully assembled RNA or RNP structures, and the efficient unwinding of short duplexes is adapted to the separation of duplexes in physiological RNAs and RNPs, which rarely exceed one helical turn.…”

Section: Mitochondrial Rna Editingmentioning

confidence: 99%

“…Several structural changes accompany different stages of the ATP binding and hydrolysis cycle of DEAD box proteins. It is well established that the two RecA-like domains of the helicase core move relatively freely with respect to each other in the absence of RNA and ATP 26 . Kinetic data suggest that ATP binding in the presence of RNA…”

Section: Mitochondrial Rna Editingmentioning

confidence: 99%

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From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

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953

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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 ....

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Section: Mitochondrial Rna Editingmentioning

confidence: 99%

Section: Mitochondrial Rna Editingmentioning

confidence: 99%

Section: Mitochondrial Rna Editingmentioning

confidence: 99%

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From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

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953

1,069

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“…RNA chaperones that rescue misfolded structures allow an escape from these opposing demands for catalytic and folding efficiency by relieving selective pressure against slow-folding or misfolding RNAs. Members of the DExD/H-box protein family, principally from the major subfamily DEADbox (the eponymous DEAD motif is one-letter code for the amino-acid sequence Asp-GluAla-Asp), are involved in virtually every cellular process involving RNA, ranging from splicing, transport, localization, translation, and decay [23,33]. Although DEAD-box proteins have been casually referred to as "RNA helicases" on the basis of their structural similarity to DNA helicases, they are unlikely to processively unwind helices, as RNA rarely contains the long helical stretches found in genomic DNA.…”

Section: How Atp-dependent Rna Chaperones Assist Foldingmentioning

confidence: 99%

“…Fortunately, there are insightful reviews in these omitted areas (e.g., [20][21][22][23][24][25][26][27][28]). It is a remarkable testament to those in the rather small world of RNA folding and function that so much progress has been made in the relatively short time of modern studies of RNA folding and dynamics.…”

mentioning

confidence: 99%

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

Chu

Herschlag

2008

Current Opinion in Structural Biology

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SummaryThe rapid development of our understanding of the diverse biological roles fulfilled by non-coding RNA has motivated interest in the basic macromolecular behavior, structure, and function of RNA. We focus on two areas in the behavior of complex RNAs. First, we present advances in the understanding of how RNA folding is accomplished in vivo by presenting a mechanism for the action of DEAD-box proteins. Members of this family are intimately associated with almost all cellular processes involving RNA, mediating RNA structural rearrangements and chaperoning their folding. Next, we focus on advances in understanding and characterizing the basic biophysical forces that govern the folding of complex RNAs. Ultimately we expect that a confluence and synergy between these approaches will lead to profound understanding of RNA and its biology.The explosion in our knowledge about noncoding RNA (ncRNA) -RNA that is not translated into protein -has expanded interest in RNA beyond the traditional RNA community. Diverse ncRNAs include the recently-discovered riboswitches, whose novel gene-regulation function is induced by the binding of small metabolites [1]; most of the so-called "Human Accelerated Regions" (HAR) of the human genome, whose recent evolution may be linked to the emergence of the human brain [2]; and many ncRNAs of unknown function [3]. These discoveries underscore the need to understand the fundamental macromolecular behavior of RNA, its structure and dynamics, and how these RNAs are handled and exploited in biology.Study of catalytic RNAs, which allow detection of correct folding via activity measurements, has established basic thermodynamic and kinetic properties of RNA folding. Large catalytic RNAs such as the group I intron from Tetrahymena thermophila and the RNase P RNA from Bacillus subtilis fold at vastly different rates under different conditions upon addition of Mg 2+ and have been shown to fold via multiple parallel pathways, in which different molecules follow different routes with different rates and intermediates, to a common final folded structure [4,5]. These observations support the common view that RNAs traverse rugged energy landscapes as they fold [6,7]. However, little is known about the true shape of these

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DNA Helicases: Chemistry and Mechanisms

Pugh

Spies

2008

Wiley Encyclopedia of Chemical Biology

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DNA helicases are members of a larger class of enzymes composed of molecular motors that couple the energy of NTP binding and hydrolysis to directional translocation along a nucleic acid lattice. Structurally and mechanistically related helicases perform drastically different roles in DNA metabolism by associating with various macromolecular machineries that orchestrate DNA processing events. Within these macromolecular ensembles, DNA helicase translocation is coupled to separation of duplex DNA into two single strands, which is necessary for DNA replication, repair, recombination and transcription. Translocation by DNA helicases can also result in the disassembly of protein–nucleic acid complexes formed during DNA metabolism. One major consequence of cellular dependence on DNA helicases is that defects in these enzymes result in a broad spectrum of disorders usually characterized by premature aging, susceptibility to cancer, and other diseases normally associated with aging.

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RNA helicases — one fold for many functions

Cited by 236 publications

References 82 publications

From unwinding to clamping — the DEAD box RNA helicase family

From unwinding to clamping — the DEAD box RNA helicase family

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

DNA Helicases: Chemistry and Mechanisms

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