Eukaryotic initiation factor 4F

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Solution structure of yeast eIF4E bound to the m7G cap and a eIF4G fragment (PDB 1RF8). EIF4G-eIF4E-m7G solution structure.png
Solution structure of yeast eIF4E bound to the m7G cap and a eIF4G fragment (PDB 1RF8).

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. [2] [3] The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since. [3]

Contents

Function

eIF4F is important for recruiting the small ribosomal subunit (40S) to the 5' cap of mRNAs during cap-dependent translation initiation. Components of the complex are also involved in cap-independent translation initiation; for instance, certain viral proteases cleave eIF4G to remove the eIF4E-binding region, thus inhibiting cap-dependent translation. [3]

Structure

Structures of eIF4F components have been solved individually and as partial complexes by a variety of methods, but no complete structure of eIF4F is currently available. [4]

Subunits

In mammals, the eIF4E•G•A trimeric complex can be directly purified from cells, while only the two subunit eIF4E•G can be purified from yeast cells. [3] eIF4E binds the m7G 5' cap and the eIF4G scaffold, connecting the mRNA 5' terminus to a hub of other initiation factors and mRNA. The interaction of eIF4G•A is thought to guide the formation of a single-stranded RNA landing pad for the 43S preinitiation complex (43S PIC) via eIF4A's RNA helicase activity. [3]

The eIF4F proteins interact with a number of different binding partners, and there are multiple genetic isoforms of eIF4A, eIF4E, and eIF4G in the human genome. In mammals, eIF4F is bridged to the 40S ribosomal subunit by eIF3 via eIF4G, while budding yeast lacks this connection. [3] Interactions between eIF4G and PABP are thought to mediate the circularization of mRNA particles. [5]

SubunitMW (kDa) [A] IsoformsKey Features
eIF4A 46 eIF4A1, eIF4A2, eIF4A3 DEAD-box RNA helicase. Binds mRNA, eIF4G, eIF4B, eIF4H, and PDCD4. Inhibited by the small molecules hippuristanol, [6] rocaglamide A (RocA), [7] and pateamine A. [8]
eIF4E 25 eIF4E1, eIF4E2, eIF4E3 Cap-binding protein. Binds eIF4G, 4EBP1, 4EBP2 and 4EBP3.
eIF4G 175 eIF4G1, eIF4G3 "Scaffold" protein. Binds mRNA, eIF4A, eIF4E, and PABP.

A Approximate molecular weight for human proteins.

In addition to the major proteins encompassing the eIF4F trimer, the eIF4F complex functionally interacts with proteins including eIF4B and eIF4H. The unusual isoform of eIF4G, eIF4G2 or DAP5, also appears to perform a non-canonical translation function.

Regulation

The eIF4E subunit of eIF4F is an important target of mTOR signaling through the eIF4E binding protein (4E-BP). [3] Phosphorylation of 4E-BPs by mTOR prevents their binding to eIF4E, freeing eIF4E to bind eIF4G and participate in translation initiation. [3]

See also

Related Research Articles

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Ribosome Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes ( ), also called Palade granules, are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA (rRNA) molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

Transcription preinitiation complex Complex of proteins necessary for gene transcription in eukaryotes and archaea

The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.

An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. In eukaryotic translation, initiation typically occurs at the 5' end of mRNA molecules, since 5' cap recognition is required for the assembly of the initiation complex. The location for IRES elements is often in the 5'UTR, but can also occur elsewhere in mRNAs.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping.

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

Eukaryotic transcription Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

NSP3 (rotavirus)

Rotavirus protein NSP3 (NS34) is bound to the 3' end consensus sequence of viral mRNAs in infected cells.

EIF4E

Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.

Eukaryotic translation initiation factor 4 gamma 1

Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the EIF4G1 gene.

DEAD box

DEAD box proteins are involved in an assortment of metabolic processes that typically involve RNAs, but in some cases also other nucleic acids. They are highly conserved in nine motifs and can be found in most prokaryotes and eukaryotes, but not all. Many organisms, including humans, contain DEAD-box (SF2) helicases, which are involved in RNA metabolism.

EIF4A1 Protein coding gene in Humans

Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.

EIF4B

Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.

EIF1

Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

Eukaryotic Initiation Factor 2 (eIF2) is a eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

Eukaryotic initiation factor 3

Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor. The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits.

References

  1. ↑ Gross, John D.; Moerke, Nathan J.; von der Haar, Tobias; Lugovskoy, Alexey A.; Sachs, Alan B.; McCarthy, John E.G.; Wagner, Gerhard (2003). "Ribosome Loading onto the mRNA Cap Is Driven by Conformational Coupling between eIF4G and eIF4E". Cell. Elsevier BV. 115 (6): 739–750. doi: 10.1016/s0092-8674(03)00975-9 . ISSN   0092-8674. PMID   14675538.
  2. ↑ Aitken CE, Lorsch JR (June 2012). "A mechanistic overview of translation initiation in eukaryotes". Nature Structural & Molecular Biology. 19 (6): 568–76. doi:10.1038/nsmb.2303. PMID   22664984. S2CID   9201095.
  3. 1 2 3 4 5 6 7 8 Merrick WC (October 2015). "eIF4F: a retrospective". The Journal of Biological Chemistry. 290 (40): 24091–9. doi: 10.1074/jbc.R115.675280 . PMC   4591800 . PMID   26324716.
  4. ↑ Fraser CS (July 2015). "Quantitative studies of mRNA recruitment to the eukaryotic ribosome". Biochimie. 114: 58–71. doi:10.1016/j.biochi.2015.02.017. PMC   4458453 . PMID   25742741.
  5. ↑ Wells SE, Hillner PE, Vale RD, Sachs AB (July 1998). "Circularization of mRNA by eukaryotic translation initiation factors". Molecular Cell. 2 (1): 135–40. doi:10.1016/S1097-2765(00)80122-7. PMID   9702200.
  6. ↑ Cencic R, Pelletier J (January 2016). "Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A". Translation. 4 (1): e1137381. doi:10.1080/21690731.2015.1137381. PMC   4909409 . PMID   27335721.
  7. ↑ Iwasaki S, Floor SN, Ingolia NT (June 2016). "Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor". Nature. 534 (7608): 558–61. Bibcode:2016Natur.534..558I. doi:10.1038/nature17978. PMC   4946961 . PMID   27309803.
  8. ↑ Low WK, Dang Y, Schneider-Poetsch T, Shi Z, Choi NS, Merrick WC, Romo D, Liu JO (December 2005). "Inhibition of eukaryotic translation initiation by the marine natural product pateamine A". Molecular Cell. 20 (5): 709–22. doi: 10.1016/j.molcel.2005.10.008 . PMID   16337595.
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