scholarly journals Structural basis for transcriptional start site control of HIV-1 RNA fate

Science ◽  
2020 ◽  
Vol 368 (6489) ◽  
pp. 413-417 ◽  
Author(s):  
Joshua D. Brown ◽  
Siarhei Kharytonchyk ◽  
Issac Chaudry ◽  
Aishwarya S. Iyer ◽  
Hannah Carter ◽  
...  
Keyword(s):  
Transcriptional Start Site ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Structural Basis ◽  
Energetic Cost ◽  
Messenger Rnas ◽  
Start Site ◽  
Eukaryotic Translation ◽  
Central Helix ◽  
Hiv 1

Heterogeneous transcriptional start site usage by HIV-1 produces 5′-capped RNAs beginning with one, two, or three 5′-guanosines (Cap1G, Cap2G, or Cap3G, respectively) that are either selected for packaging as genomes (Cap1G) or retained in cells as translatable messenger RNAs (mRNAs) (Cap2G and Cap3G). To understand how 5′-guanosine number influences fate, we probed the structures of capped HIV-1 leader RNAs by deuterium-edited nuclear magnetic resonance. The Cap1G transcript adopts a dimeric multihairpin structure that sequesters the cap, inhibits interactions with eukaryotic translation initiation factor 4E, and resists decapping. The Cap2G and Cap3G transcripts adopt an alternate structure with an elongated central helix, exposed splice donor residues, and an accessible cap. Extensive remodeling, achieved at the energetic cost of a G-C base pair, explains how a single 5′-guanosine modifies the function of a ~9-kilobase HIV-1 transcript.

scholarly journals Focus on Translation Initiation of the HIV-1 mRNAs

2018 ◽  
Vol 20 (1) ◽  
pp. 101 ◽  
Author(s):  
Sylvain de Breyne ◽  
Théophile Ohlmann
Keyword(s):  
Translation Initiation ◽  
Translational Control ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cellular Proteins ◽  
Internal Ribosome Entry ◽  
Eukaryotic Translation ◽  
Cellular Environment ◽  
Key Steps ◽  
Hiv 1

To replicate and disseminate, viruses need to manipulate and modify the cellular machinery for their own benefit. We are interested in translation, which is one of the key steps of gene expression and viruses that have developed several strategies to hijack the ribosomal complex. The type 1 human immunodeficiency virus is a good paradigm to understand the great diversity of translational control. Indeed, scanning, leaky scanning, internal ribosome entry sites, and adenosine methylation are used by ribosomes to translate spliced and unspliced HIV-1 mRNAs, and some require specific cellular factors, such as the DDX3 helicase, that mediate mRNA export and translation. In addition, some viral and cellular proteins, including the HIV-1 Tat protein, also regulate protein synthesis through targeting the protein kinase PKR, which once activated, is able to phosphorylate the eukaryotic translation initiation factor eIF2α, which results in the inhibition of cellular mRNAs translation. Finally, the infection alters the integrity of several cellular proteins, including initiation factors, that directly or indirectly regulates translation events. In this review, we will provide a global overview of the current situation of how the HIV-1 mRNAs interact with the host cellular environment to produce viral proteins.

scholarly journals A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1

2018 ◽  
Vol 74 (3) ◽  
pp. 156-160 ◽  
Author(s):  
Yumi Matsui ◽  
Isao Yasumatsu ◽  
Ken-ichi Yoshida ◽  
Shin Iimura ◽  
Yutaka Ikeno ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Translation Initiation ◽  
Kinase Activity ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Structural Basis ◽  
Eukaryotic Translation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation

Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors.

scholarly journals Structural basis for eIF2B inhibition in integrated stress response

Science ◽  
2019 ◽  
Vol 364 (6439) ◽  
pp. 495-499 ◽  
Author(s):  
Kazuhiro Kashiwagi ◽  
Takeshi Yokoyama ◽  
Madoka Nishimoto ◽  
Mari Takahashi ◽  
Ayako Sakamoto ◽  
...  
Keyword(s):  
Stress Response ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Structural Basis ◽  
Dependent Manner ◽  
Integrated Stress Response ◽  
Nucleotide Exchange ◽  
Electron Microscopic ◽  
Eukaryotic Translation ◽  
Initiation Factor 2

A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers the methionylated initiator tRNA to the ribosome in a guanosine 5′-triphosphate–dependent manner. By contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor, eIF2B. To elucidate how the eIF2 phosphorylation status regulates the eIF2B activity, we determined cryo–electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. These structures explain how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.

scholarly journals Human eIF3: from ‘blobology’ to biological insight

2017 ◽  
Vol 372 (1716) ◽  
pp. 20160176 ◽  
Author(s):  
Jamie H. D. Cate
Keyword(s):  
Translation Initiation ◽  
Molecular Mechanisms ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Messenger Rnas ◽  
Internal Ribosome Entry ◽  
General Role ◽  
Eukaryotic Translation ◽  
Biological Insight ◽  
Eukaryotic Translation Initiation

Translation in eukaryotes is highly regulated during initiation, a process impacted by numerous readouts of a cell's state. There are many cases in which cellular messenger RNAs likely do not follow the canonical ‘scanning’ mechanism of translation initiation, but the molecular mechanisms underlying these pathways are still being uncovered. Some RNA viruses such as the hepatitis C virus use highly structured RNA elements termed internal ribosome entry sites (IRESs) that commandeer eukaryotic translation initiation, by using specific interactions with the general eukaryotic translation initiation factor eIF3. Here, I present evidence that, in addition to its general role in translation, eIF3 in humans and likely in all multicellular eukaryotes also acts as a translational activator or repressor by binding RNA structures in the 5′-untranslated regions of specific mRNAs, analogous to the role of the mediator complex in transcription. Furthermore, eIF3 in multicellular eukaryotes also harbours a 5′ 7-methylguanosine cap-binding subunit—eIF3d—which replaces the general cap-binding initiation factor eIF4E in the translation of select mRNAs. Based on results from cell biological, biochemical and structural studies of eIF3, it is likely that human translation initiation proceeds through dozens of different molecular pathways, the vast majority of which remain to be explored. This article is part of the themed issue ‘Perspectives on the ribosome’.

Sign in / Sign up

Export Citation Format

Share Document