Topology and Regulation of the Human eIF4A/4G/4H Helicase Complex in Translation Initiation

Marintchev, Assen; Edmonds, Katherine A.; Marintcheva, Boriana; Hendrickson, Elthea; Oberer, Monika; Suzuki, Chikako; Herdy, Barbara; Sonenberg, Nahum; Wagner, Gerhard

doi:10.1016/j.cell.2009.01.014

Cited by 207 publications

(279 citation statements)

References 31 publications

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“…4). Other studies suggest that eIF4G, together with eIF4A and eIF4H, promotes ribosome scanning 88 . These scenarios are not mutually exclusive and it is possible that several distinct complexes are formed by eIF4A and eIF4G in response to different signals or on different RNAs.…”

Section: Nuclear Specklesmentioning

confidence: 95%

“…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%

“…The cap-binding complex eIF4F is composed of the cap-binding protein eIF4E, the scaffolding protein eIF4G and the translation initiation factor eIF4A. The 40S initiation complex then scans through the 5′ untranslated region for the first AUG initiator codon to begin translation 76,88,92 . Association of programmed cell death 4 (PDCD4) with two molecules of eIF4A (middle) triggers a conformational change that prevents association with eIF4G and thereby inhibits the initiation of translation.…”

Section: Nuclear Specklesmentioning

confidence: 99%

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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: 95%

Section: Nuclear Specklesmentioning

confidence: 99%

Section: Nuclear Specklesmentioning

confidence: 99%

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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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“…Equilibrium dissociation constants can be obtained directly in fluorescence titrations of fluorescently labeled nucleotides or RNA. Nucleotide binding can be investigated via fluorescence of mant nucleotides (Henn et al, 2002(Henn et al, , 2008Talavera and De La Cruz, 2005;Karow et al, 2007;Theissen et al, 2008;Karow and Klostermeier, 2009), and RNA binding can be monitored via fluorescence anisotropy using fluorescently labeled RNAs (Karow et al, 2007;Marintchev et al, 2009). Fluorescence spectroscopy has also been employed to directly determine rate constants for nucleotide binding and dissociation (Henn et al, 2002(Henn et al, , 2008 and for RNA unwinding (Karow et al, 2007).…”

Section: Interaction Of Dead Box Proteins With Adenine Nucleotides Anmentioning

confidence: 99%

“…A prominent example for such a regulation mechanism is eIF4A. Its intrinsically very weak helicase activity is stimulated by various other translation factors (Rogers et al, 2001a;Korneeva et al, 2005;Oberer et al, 2005;Schutz et al, 2008;Marintchev et al, 2009). A well-studied example is the functional interaction of eIF4A with eIF4G.…”

Section: Regulation By Other Protein Factorsmentioning

confidence: 99%

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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Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

Kang

2023

FEBS Letters

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RNA‐binding proteins (RBPs) play vital roles in organisms through binding with RNAs to regulate their functions. Small molecules affecting the function of RBPs have been developed, providing new avenues for drug discovery. Herein, we describe the perspectives on developing small molecule regulators of RBPs. The following types of small molecule modulators are of great interest in drug discovery: small molecules binding to RBPs to affect interactions with RNA molecules, bifunctional molecules binding to RNA or RBP to influence their interactions, and other types of molecules that affect the stability of RNA or RBPs. Moreover, we emphasize that the bifunctional molecules may play important roles in small molecule development to overcome the challenges encountered in the process of drug discovery.

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Topology and Regulation of the Human eIF4A/4G/4H Helicase Complex in Translation Initiation

Cited by 207 publications

References 31 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

Targeting RNA‐binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules

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