The iron–sulphur protein RNase L inhibitor functions in translation termination

Khoshnevis, Sohail; Gross, Thomas P.; Rotte, Carmen; Baierlein, Claudia; Ficner, Ralf; Krebber, Heike

doi:10.1038/embor.2009.272

Cited by 120 publications

(167 citation statements)

References 17 publications

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…In addition, ABCE1 protein has been suggested new important roles in translation termination and ribosome recycling in eukaryotes. Studies of yeast genetic showed that ABCE1 protein interacts physically with the termination factor eRF1 and, to a lesser extent, eRF3 (33). The same study demonstrated that downregulation of ABCE1 protein leads to defects in the recognition of a stop codon.…”

Section: Abce1 Protein Relates Closely With Eukaryotic Translationmentioning

confidence: 88%

The biological regulation of ABCE1

2012

View full text Add to dashboard Cite

SummaryATP binding cassette E1 (ABCE1) protein, also named RLI or HP68, is one member of ATP binding cassette superfamily. By forming a heterodimer with RNase L, ABCE1 protein inhibits the IFN-depended 2-5A/RNase L system and regulates a broad range of biological functions including viral infection, tumor cell proliferation, and antiapoptosis. As a highly conserved protein, recent studies have mainly focused that ABCE1 protein is involving in the fields of HIV virus capsids assembly and important roles in translation. Our manuscript will review the studies which revealed the biological regulation of ABCE1.

show abstract

Section: Abce1 Protein Relates Closely With Eukaryotic Translationmentioning

confidence: 88%

The biological regulation of ABCE1

2012

View full text Add to dashboard Cite

show abstract

“…If this is the case, efficient release of eRF3 could be promoted by ABCE1, whose ribosome-binding site overlaps with that of eRF3 (38). Dissociation of eRF3 might in turn accelerate accommodation of eRF1's domain M, which would at least in part account for stimulation of peptide release by ABCE1 (6,39).…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

Taylor

Unbehaun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Eukaryotic translation termination results from the complex functional interplay between two eukaryotic release factors, eRF1 and eRF3, and the ribosome, in which GTP hydrolysis by eRF3 couples codon recognition with peptidyl-tRNA hydrolysis by eRF1. Here, using cryo-electron microscopy (cryo-EM) and flexible fitting, we determined the structure of eRF1-eRF3-guanosine 5′- [β,γ-imido] triphosphate (GMPPNP)-bound ribosomal pretermination complex (pre-TC), which corresponds to the initial, pre-GTP hydrolysis stage of factor attachment. Our results show that eukaryotic translation termination involves a network of interactions between the two release factors and the ribosome. Our structure provides mechanistic insight into the coordination between GTP hydrolysis by eRF3 and subsequent peptide release by eRF1.T ermination of translation occurs when a ribosome reaches the end of the coding region and a stop codon (UAA, UAG, or UGA) enters the aminoacyl tRNA binding site (A site), leaving peptidyl-tRNA in the peptidyl tRNA binding site (P site). It entails stop codon recognition by specialized release factors followed by hydrolysis of peptidyl-tRNA. In eukaryotes, termination is mediated by the concerted action of two directly interacting release factors, eRF1 and eRF3. eRF1 is responsible for stop codon recognition and inducing hydrolysis of peptidyl-tRNA, whereas eRF3, a ribosome-dependent GTPase, strongly stimulates peptide release by eRF1 in a GTP-dependent manner (for review, see ref. 1).eRF1 also participates in ribosome recycling: after peptide release it remains associated with the ribosome and together with ATP-binding cassette sub-family E member 1 (ABCE1) promotes splitting the ribosome into free 60S and tRNA/mRNA-associated 40S subunits (2). eRF1 and eRF3 have paralogs, Dom34 (yeast)/ Pelota (mammals) and Hbs1, respectively, which do not participate in termination but instead play a key role in No-go and nonstop decay surveillance mechanisms (e.g., see refs. 3, 4). Dom34/Pelota and Hbs1 do not induce peptide release in a mechanism similar to eRFs. Instead, they cooperate with ABCE1 to promote dissociation of stalled elongation complexes, which is accompanied by peptidyltRNA drop off (5-7). eRF1 comprises N-terminal (N), middle (M), and C-terminal (C) domains (8). The N domain is responsible for stop codon recognition, which is achieved through a 3D network of conserved residues that include apical TASNIKS (amino acid sequence: threonine-alanine-serine-asparagine-isoleucine-lysine-serine) and YxCxxxF motifs (e.g., refs. 9-12). Domain M contains the universally conserved GGQ motif, which is critical for triggering peptide release: as shown for prokaryotes, its placement into the peptidyl transferase center (PTC) causes rRNA rearrangement, allowing a water molecule to enter (for review, see ref. 13). The rigid core of domain C forms an α-β sandwich (8) that deviates from the standard form by the presence of a small insertion, which forms a minidomain (14). eRF3 consists of an N-terminal sequence (residues 1-...

show abstract

“…ATP-binding cassette family E1 (ABCE1), a host protein formerly known as "HP68" (40) and "RNase L inhibitor" (41), has been implicated in various activities including ribosome recycling (42)(43)(44)(45)(46) and HIV capsid assembly (8-11, 13, 40).…”

mentioning

confidence: 99%

Host–rabies virus protein–protein interactions as druggable antiviral targets

Lingappa¹,

Macieik³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We present an unconventional approach to antiviral drug discovery, which is used to identify potent small molecules against rabies virus. First, we conceptualized viral capsid assembly as occurring via a hostcatalyzed biochemical pathway, in contrast to the classical view of capsid formation by self-assembly. This suggested opportunities for antiviral intervention by targeting previously unappreciated catalytic host proteins, which were pursued. Second, we hypothesized these host proteins to be components of heterogeneous, labile, and dynamic multi-subunit assembly machines, not easily isolated by specific target protein-focused methods. This suggested the need to identify active compounds before knowing the precise protein target. A cell-free translation-based small molecule screen was established to recreate the hypothesized interactions involving newly synthesized capsid proteins as host assembly machine substrates. Hits from the screen were validated by efficacy against infectious rabies virus in mammalian cell culture. Used as affinity ligands, advanced analogs were shown to bind a set of proteins that effectively reconstituted drug sensitivity in the cell-free screen and included a small but discrete subfraction of cellular ATP-binding cassette family E1 (ABCE1), a host protein previously found essential for HIV capsid formation. Taken together, these studies advance an alternate view of capsid formation (as a host-catalyzed biochemical pathway), a different paradigm for drug discovery (whole pathway screening without knowledge of the target), and suggest the existence of labile assembly machines that can be rendered accessible as next-generation drug targets by the means described.assembly intermediate | viral-host interaction | whole pathway screen | drug discovery paradigm | protein heterogeneity

show abstract

The iron–sulphur protein RNase L inhibitor functions in translation termination

Cited by 120 publications

References 17 publications

The biological regulation of ABCE1

The biological regulation of ABCE1

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

Host–rabies virus protein–protein interactions as druggable antiviral targets

Contact Info

Product

Resources

About