Substrate-Dependent Targeting of Eukaryotic Translation Initiation Factor 4A by Pateamine A: Negation of Domain-Linker Regulation of Activity

Low, Woon Kai; Dang, Yongjun; Bhat, Shridhar; Romo, Daniel; Liu, Jun O.

doi:10.1016/j.chembiol.2007.05.012

Cited by 55 publications

(54 citation statements)

References 47 publications

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“…We have previously shown that PatA may act by "trapping" eIF4AI in a "closed" conformation, which leads to its increased enzymatic activity and prevents the necessary cycling through the different conformational states associated with its normal function (30). The increased association of RNA with the EJC in the presence of DMDA-PatA and the inhibition of NMD observed here suggest that PatA may exert similar conformational effects on eIF4AIII.…”

Section: Discussionsupporting

confidence: 52%

“…The eIF4A proteins are the prototypical D-E-A-D box proteins, having RNA-dependent ATPase activity and ATP-dependent RNA helicase activity (33). In addition to eIF4AI/II, PatA was also shown to bind the closely related homolog eIF4AIII and stimulate its ATPase activity (30,32). The main cellular function of eIF4AIII is to serve as a core component of the EJC (34 -38).…”

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confidence: 99%

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Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII

Dang¹,

Low²,

Xu³

et al. 2009

Journal of Biological Chemistry

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Nonsense-mediated mRNA decay (NMD) in mammalian cells is a key mechanism for the removal of mRNA containing premature stop codons and is mediated by the coordinated function of numerous proteins that dynamically associate with the exon junction complex. The information communicated by these interactions and the functional consequences from a mechanistic perspective, however, are not completely documented. Herein, we report that the natural product pateamine A (PatA) is capable of inhibiting NMD through direct interaction with eIF4AIII, which is independent of its inhibition of translation initiation. Furthermore, we have characterized the mechanisms by which PatA and cycloheximide modulate NMD. Unlike CHX, PatA was found to inhibit NMD by a novel mechanism that is independent of the phosphorylation of Up-frameshift protein 1.In mammalian cells, nonsense-mediated mRNA decay (NMD) 2 is one of the key RNA surveillance mechanisms to specifically degrade mRNA with premature stop codons (PTCs) located more than 50 -55 nucleotides upstream of the final exon-exon junction. PTCs can be formed in genes containing a nonsense mutation or frameshift mutation or as a result of errors that occur during transcription or RNA splicing (1-4). After splicing, the exon junction complex (EJC) imprints mature mRNAs 20 -24 nucleotides upstream of the exon-exon junction (5). The EJC is a dynamic multiprotein complex that plays an essential role in NMD. The core EJC proteins eIF4AIII, Y14, Magoh, and MLN51 form a platform to interact with several other proteins in a dynamic fashion to regulate NMD (6). The spatial-temporal regulation of NMD by the EJC and its partner proteins has been extensively investigated, leading to the proposition of the "linear interaction model" (4, 7). According to this model, deposition of the EJC onto mRNA causes the Y14-Magoh and eIF4AIII complex to effectively recruit Upf3 that interacts with Upf2. Although the mechanism of loading Upf1 onto EJC is poorly understood, it has been shown that phosphorylation and dephosphorylation of Upf1 by SMG-1, -5, -6, and -7 affect the interaction with the EJC complex through

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 99%

Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII

Dang¹,

Low²,

Xu³

et al. 2009

Journal of Biological Chemistry

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“…In addition, the lack of contributions of the g-phosphate to nucleotide affinity is an indication for ATP-driven conformational changes. Limited proteolysis experiments provide further evidence for ATP-induced conformational changes (Lorsch and Herschlag, 1998b;Henn et al, 2002;Cheng et al, 2005;Low et al, 2007).…”

Section: Nucleotide Bindingmentioning

confidence: 89%

“…Indirect evidence for such a conformational reorganization is available from different proteolysis patterns in the presence or absence of substrates (Lorsch and Herschlag, 1998b;Henn et al, 2002;Cheng et al, 2005;Low et al, 2007). Nucleotide binding kinetics support nucleotide-driven conformational rearrangements: ATP and ADP binding follows a single exponential in the absence of RNA, but a second slow phase appears when RNA is present.…”

Section: Cooperativity Of Rna and Nucleotide Bindingmentioning

confidence: 99%

“…In contrast to the similar arrangement of the two domains, the connecting linker region adopts different conformations in the closed structures of eIF4AIII, Vasa, and Ddx19. Stepwise conversion of the eIF4A linker to the corresponding Vasa sequence resulted in enhanced ATPase activity, revealing the linker as a regulatory element (Low et al, 2007).…”

Section: Introductionmentioning

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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Concise Synthesis of a Pateamine A Analogue with In Vivo Anticancer Activity Based on an Iron‐Catalyzed Pyrone Ring Opening/Cross‐Coupling

Zhuo

Fürstner

2016

Angewandte Chemie

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The marine macrolide pateamine A and its non‐natural sibling DMDA‐Pat A are potent translation inhibitors targeting the eukaryotic initiation factor 4A (eIF4A), an enzyme with RNA helicase activity. Although essential for every living cell, this protein target seems “drugable” since DMDA‐Pat A has previously been shown to exhibit remarkable in vivo activity against two different melanoma mouse models. The novel entry into this promising compound presented herein is shorter and significantly more productive than the literature route. Key to success was the masking of the signature Z,E‐configured dienoate subunit of DMDA‐Pat A in the form of a 2‐pyrone ring, which was best crafted by a gold‐catalyzed cyclization. While the robustness of the heterocycle facilitated the entire assembly stage, the highly isomerization‐prone seco‐Z,E‐dienoic acid could be unlocked in due time for macrolactonization by an unconventional iron‐catalyzed ring opening/cross coupling. Moreover, the crystal structure analysis of an advanced intermediate gave first insights into the conformation of the macrodilactone framework of the pateamine family, which is thought to be critical for eliciting the desired biological response.

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Substrate-Dependent Targeting of Eukaryotic Translation Initiation Factor 4A by Pateamine A: Negation of Domain-Linker Regulation of Activity

Cited by 55 publications

References 47 publications

Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII

Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII

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

Concise Synthesis of a Pateamine A Analogue with In Vivo Anticancer Activity Based on an Iron‐Catalyzed Pyrone Ring Opening/Cross‐Coupling

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