Interactions between eIF4AI and its accessory factors eIF4B and eIF4H

Rozovsky, Nadja; Butterworth, Aimee C.; Moore, Melissa J.

doi:10.1261/rna.1049608

Cited by 91 publications

(110 citation statements)

References 46 publications

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“…However, an appreciable fraction of eIF4A is not bound in eIF4F 77 . eIF4A also associates with the initiation factors eIF4B and eIF4H, which are closely related RNA-binding proteins that enhance eIF4A association with RNA 84 and thereby increase the ability of eIF4A to unwind RNA and hydrolyse ATP in an RNA-stimulated fashion 85,86,87 . Together, these factors all promote formation of a translation initiation complex that allows binding of the small 40S ribosomal unit and other initiation factors to mRNA 88 .…”

Section: Nuclear Specklesmentioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

983

1,069

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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: Nuclear Specklesmentioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

983

1,069

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“…Regulation of eIF4A activity by other translation factors might follow a similar regulation principle. For eIF4B and eIF4H, stable interactions with the N-terminal domain of eIF4A in the presence of ADPNP and ssRNA have been demonstrated, and there is evidence for additional interactions with the C-terminal domains (Rozovsky et al, 2008).…”

Section: Regulation By Other Protein Factorsmentioning

confidence: 99%

“…In contrast, the ADP-P i state exhibits high RNA affinity (Henn et al, 2008). Non-hydrolyzable ATP analogs, such as ADPNP, ADP-BeF x , and ADP-AlF x , promote high affinity RNA binding (Ballut et al, 2005;Liu et al, 2008;Nielsen et al, 2008;Rozovsky et al, 2008;Theissen et al, 2008), but different results have been obtained for ATP itself: high RNA affinity was reported for the ATP state of DbpA (Polach and Uhlenbeck, 2002;Elles and Uhlenbeck, 2008), whereas the ATP states of Dbp5 and eIF4A exhibit low RNA affinity (Nielsen et al, 2008;Rozovsky et al, 2008).…”

Section: Coupling Of Atp Hydrolysis and Duplex Separationmentioning

confidence: 99%

“…Since then, functional interaction with unstructured RNAs of ;15 nucleotides was shown for several DEAD box helicases (Peck and Herschlag, 1999;Bizebard et al, 2004;Garcia and Uhlenbeck, 2008). RNA protection experiments showed that ;10 nucleotides are protected by binding to eIF4A (Le Hir et al, 2000;Ballut et al, 2005;Rozovsky et al, 2008). However, already 2-4 RNA nucleotides within a DNA molecule lead to a stimulation of ATPase activity (Peck and Herschlag, 1999).…”

Section: Rna Bindingmentioning

confidence: 99%

“…Interacting proteins might also increase the size of the RNA binding site. The RNA binding site of eIF4A increases from ;17 to ;30 nucleotides in the presence of its interacting partners eIF4H or eIF4B (Rozovsky et al, 2008), and to )60 bp in the eIF4F complex (Kaye et al, 2009). Altogether, it appears that binding already occurs with rather short RNA molecules, but full activation of the DEAD box protein might require larger nucleic acids interacting with the core.…”

Section: Rna Bindingmentioning

confidence: 99%

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The mechanism of ATP-dependent RNA unwinding by DEAD box proteins

Hilbert

Karow²,

Klostermeier³

2009

BCHM

143

171

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DEAD box proteins catalyze the ATP-dependent unwinding of double-stranded RNA (dsRNA). In addition, they facilitate protein displacement and remodeling of RNA or RNA/protein complexes. Their hallmark feature is local destabilization of RNA duplexes. Here, we summarize current data on the DEAD box protein mechanism and present a model for RNA unwinding that integrates recent data on the effect of ATP analogs and mutations on DEAD box protein activity. DEAD box proteins share a conserved helicase core with two flexibly linked RecAlike domains that contain all helicase signature motifs. Variable flanking regions contribute to substrate binding and modulate activity. In the presence of ATP and RNA, the helicase core adopts a compact, closed conformation with extensive interdomain contacts and high affinity for RNA. In the closed conformation, the RecA-like domains form a catalytic site for ATP hydrolysis and a continuous RNA binding site. A kink in the backbone of the bound RNA locally destabilizes the duplex. Rearrangement of this initial complex generates a hydrolysisand unwinding-competent state. From this complex, the first RNA strand can dissociate. After ATP hydrolysis and phosphate release, the DEAD box protein returns to a low-affinity state for RNA. Dissociation of the second RNA strand and reopening of the cleft in the helicase core allow for further catalytic cycles.

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Virus‐encoded endonucleases: expected and novel functions

Read

2013

WIREs RNA

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Endonucleases catalyze critical steps in the processing, function, and turnover of many cellular RNAs. It is, therefore, not surprising that a number of viruses encode endonucleases that play important roles in viral gene expression. The virion host shutoff (Vhs) endonuclease of herpes simplex virus, the SOX protein of Kaposi Sarcoma Herpesvirus (KSHV), and the influenza virus PB1 endonuclease have well-characterized functions that stem from their abilities to cleave RNA. Vhs accelerates turnover of many cellular and viral mRNAs, redirecting the cell from host to viral gene expression, counteracting key elements of the innate immune response, and facilitating sequential expression of different classes of viral genes. SOX reduces synthesis of many host proteins during the lytic phase of KSHV infections. PB1 is a component of the influenza RNA polymerase that snatches capped oligonucleotides from cellular pre-mRNAs to serve as primers during viral mRNA synthesis. However, all three proteins have important second functions. Vhs stimulates translation of the 3' cistron of bicistronic mRNAs that have selected cellular internal ribosome entry sites, and stimulates polysome loading and translation of selected viral mRNAs at late times during productive infections. SOX has an alkaline exonuclease activity that is important for processing and maturation of newly synthesized copies of the KSHV genome. The influenza RNA polymerase binds the cap and 5' region of viral mRNAs and recruits eIF4G and other factors to viral mRNAs, allowing them to be translated under conditions of reduced eIF4E functionality. This review will discuss the novel and expected functions of these viral endonucleases.

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Interactions between eIF4AI and its accessory factors eIF4B and eIF4H

Cited by 91 publications

References 46 publications

From unwinding to clamping — the DEAD box RNA helicase family

From unwinding to clamping — the DEAD box RNA helicase family

The mechanism of ATP-dependent RNA unwinding by DEAD box proteins

Virus‐encoded endonucleases: expected and novel functions

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