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Coming of age around the world
Discover a wonderful world of celebrations from around the world. Featuring the world's main religions as well as some little-known ceremonies and festivals, this book takes an intriguing and colourful look at how growing up and coming of age are celebrated in many different places.
Book
A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2
Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the precise role of some of them and their mechanism of action is still not well understood. Eukaryotic initiation factor 2A (eIF2A) is a single chain 65 kDa protein that was initially believed to serve as the functional homologue of prokaryotic IF2, since eIF2A and IF2 catalyze biochemically similar reactions, i.e., they stimulate initiator Met-tRNAi binding to the small ribosomal subunit. However, subsequent identification of a heterotrimeric 126 kDa factor, eIF2 (α,β,γ) showed that this factor, and not eIF2A, was primarily responsible for the binding of Met-tRNAi to 40S subunit in eukaryotes. It was found however, that eIF2A can promote recruitment of Met-tRNAi to 40S/mRNA complexes under conditions of inhibition of eIF2 activity (eIF2α-phosphorylation), or its absence. eIF2A does not function in major steps in the initiation process, but is suggested to act at some minor/alternative initiation events such as re-initiation, internal initiation, or non-AUG initiation, important for translational control of specific mRNAs. This review summarizes our current understanding of the eIF2A structure and function.
Journal Article
The wild bull and the sacred forest : form, meaning, and change in Senegambian initiation masks
This 1992 study of the cattle-horned initiation masks of southern Senegal and Gambia weaves together art history, history and cultural anthropology to give a detailed view of Casamance cultures, as they have interacted and changed over the past two centuries.
Book
The structure of a human translation initiation complex reveals two independent roles for the helicase eIF4A
Eukaryotic translation initiation involves recruitment of the 43S pre-initiation complex to the 5′ end of mRNA by the cap-binding complex eIF4F, forming the 48S translation initiation complex (48S), which then scans along the mRNA until the start codon is recognized. We have previously shown that eIF4F binds near the mRNA exit channel of the 43S, leaving open the question of how mRNA secondary structure is removed as it enters the mRNA channel on the other side of the 40S subunit. Here we report the structure of a human 48S that shows that, in addition to the eIF4A that is part of eIF4F, there is a second eIF4A helicase bound at the mRNA entry site, which could unwind RNA secondary structures as they enter the 48S. The structure also reveals conserved interactions between eIF4F and the 43S, probaby explaining how eIF4F can promote mRNA recruitment in all eukaryotes.
The authors report the structure of a human 48S translation initiation complex, finding a second molecule of eIF4A at the mRNA entry site, apart from the one present within the cap-binding complex eIF4F. This second entry-site eIF4A may be responsible for unwinding mRNA secondary structure.
Journal Article
A widespread alternate form of cap-dependent mRNA translation initiation
Translation initiation of most mammalian mRNAs is mediated by a 5′ cap structure that binds eukaryotic initiation factor 4E (eIF4E). However, inactivation of eIF4E does not impair translation of many capped mRNAs, suggesting an unknown alternate mechanism may exist for cap-dependent but eIF4E-independent translation. We show that DAP5, an eIF4GI homolog that lacks eIF4E binding, utilizes eIF3d to facilitate cap-dependent translation of approximately 20% of mRNAs. Genome-wide transcriptomic and translatomic analyses indicate that DAP5 is required for translation of many transcription factors and receptor capped mRNAs and their mRNA targets involved in cell survival, motility, DNA repair and translation initiation, among other mRNAs. Mass spectrometry and crosslinking studies demonstrate that eIF3d is a direct binding partner of DAP5. In vitro translation and ribosome complex studies demonstrate that DAP5 and eIF3d are both essential for eIF4E-independent capped-mRNA translation. These studies disclose a widespread and previously unknown mechanism for cap-dependent mRNA translation by DAP5-eIF3d complexes.
Binding of eIF4E to the 5′ cap of mRNAs is a key early step in canonical translation initiation, but the requirement for eIF4E is not universal. Here the authors show that the eIF4G homolog DAP5 interacts with eIF3 to promote cap-dependent translation of a significant number of mRNA in an eIF4E-independent manner.
Journal Article
Structural basis for translational control by the human 48S initiation complex
The selection of an open reading frame (ORF) for translation of eukaryotic mRNA relies on remodeling of the scanning 48S initiation complex into an elongation-ready 80S ribosome. Using cryo-electron microscopy, we visualize the key commitment steps orchestrating 48S remodeling in humans. The mRNA Kozak sequence facilitates mRNA scanning in the 48S open state and stabilizes the 48S closed state by organizing the contacts of eukaryotic initiation factors (eIFs) and ribosomal proteins and by reconfiguring mRNA structure. GTPase-triggered large-scale fluctuations of 48S-bound eIF2 facilitate eIF5B recruitment, transfer of initiator tRNA from eIF2 to eIF5B and the release of eIF5 and eIF2. The 48S-bound multisubunit eIF3 complex controls ribosomal subunit joining by coupling eIF exchange to gradual displacement of the eIF3c N-terminal domain from the intersubunit interface. These findings reveal the structural mechanism of ORF selection in human cells and explain how eIF3 could function in the context of the 80S ribosome.
Cryo-electron microscopy reveals the mechanism of human translation initiation from codon scanning to subunit joining. The structures show the roles of the Kozak sequence, GTP hydrolysis by eukaryotic initiation factor 2 (eIF2) and eIF5B in 48S remodeling, as well as that of eIF3 in the control of 60S docking.
Journal Article
Mindfulness for insomnia : a four-week guided program to relax your body, calm your mind, and get the sleep you need
The authors present their professional insights and techniques for resolving insomnia by employing the Guided Mindfulness with Acceptance Treatment for Insomnia (or GMATI) program.
Book
eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation
The initiation protein eIF3d serves as an alternative cap-recognition factor for a subclass of mRNAs, such as c-Jun; the high-resolution structure of the eIF3d cap-binding domain can be modelled onto the cap structure, defining interactions that are needed for translation of these mRNAs.
An alternative 5′ mRNA capping pathway
Recruitment of the ribosome to eukaryotic messenger RNAs (mRNAs) involves interaction between the translation initiation factor, eIF4E, and a specialized nucleotide, or 'cap', at the 5′ end of the mRNA. eIF4E is inactivated under certain conditions, but translation of numerous mRNAs is maintained. Jamie Cate and colleagues describe how another initiation protein, eIF3d, serves as an alternative cap-recognition factor for a subclass of mRNAs, such as
c-Jun
. The high-resolution structure of the eIF3d cap-binding domain can be modelled onto the cap structure, defining interactions that are needed for translation of these mRNAs. They also find that
c-Jun
mRNA contains an element that inhibits eIF4E recruitment.
Eukaryotic mRNAs contain a 5′ cap structure that is crucial for recruitment of the translation machinery and initiation of protein synthesis. mRNA recognition is thought to require direct interactions between eukaryotic initiation factor 4E (eIF4E) and the mRNA cap. However, translation of numerous capped mRNAs remains robust during cellular stress, early development, and cell cycle progression
1
despite inactivation of eIF4E. Here we describe a cap-dependent pathway of translation initiation in human cells that relies on a previously unknown cap-binding activity of eIF3d, a subunit of the 800-kilodalton eIF3 complex. A 1.4 Å crystal structure of the eIF3d cap-binding domain reveals unexpected homology to endonucleases involved in RNA turnover, and allows modelling of cap recognition by eIF3d. eIF3d makes specific contacts with the cap, as exemplified by cap analogue competition, and these interactions are essential for assembly of translation initiation complexes on eIF3-specialized mRNAs
2
such as the cell proliferation regulator
c-Jun
(also known as
JUN
). The
c-Jun
mRNA further encodes an inhibitory RNA element that blocks eIF4E recruitment, thus enforcing alternative cap recognition by eIF3d. Our results reveal a mechanism of cap-dependent translation that is independent of eIF4E, and illustrate how modular RNA elements work together to direct specialized forms of translation initiation.
Journal Article