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

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. Initiation of eukaryotic translation nearly always occurs at and is dependent on the 5' cap of mRNA molecules, where the translation initiation complex forms and ribosomes engage the mRNA. IRES elements, however allow ribosomes to engage the mRNA and begin translation independently of the 5' cap.

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

In molecular biology, 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.

<span class="mw-page-title-main">4EGI-1</span> Chemical compound

4EGI-1 is a synthetic chemical compound which has been found to interfere with the growth of certain types of cancer cells in vitro. Its mechanism of action involves interruption of the binding of cellular initiation factor proteins involved in the translation of transcribed mRNA at the ribosome. The inhibition of these initiation factors prevents the initiation and translation of many proteins whose functions are essential to the rapid growth and proliferation of cancer cells.

<span class="mw-page-title-main">Hepatitis A virus internal ribosome entry site (IRES)</span>

This family represents the internal ribosome entry site (IRES) of the hepatitis A virus. HAV IRES is a 450 nucleotide long sequence located in the 735 nt long 5’ UTR of Hepatitis A viral RNA genome. IRES elements allow cap and end-independent translation of mRNA in the host cell. The IRES achieves this by mediating the internal initiation of translation by recruiting a ribosomal 40S pre-initiation complex directly to the initiation codon and eliminates the requirement for eukaryotic initiation factor, eIF4F.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

<span class="mw-page-title-main">Poly(A)-binding protein</span> RNA binding protein

Poly(A)-binding protein is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the 3' end of mRNA and was discovered by Mary Edmonds, who also characterized the poly-A polymerase enzyme that generates the poly(a) tail. The binding protein is also involved in mRNA precursors by helping polyadenylate polymerase add the poly(A) nucleotide tail to the pre-mRNA before translation. The nuclear isoform selectively binds to around 50 nucleotides and stimulates the activity of polyadenylate polymerase by increasing its affinity towards RNA. Poly(A)-binding protein is also present during stages of mRNA metabolism including nonsense-mediated decay and nucleocytoplasmic trafficking. The poly(A)-binding protein may also protect the tail from degradation and regulate mRNA production. Without these two proteins in-tandem, then the poly(A) tail would not be added and the RNA would degrade quickly.

<span class="mw-page-title-main">Nuclear cap-binding protein complex</span> RNA-binding protein

Nuclear cap-binding protein complex is a RNA-binding protein which binds to the 5' cap of pre-mRNA. The cap and nuclear cap-binding protein have many functions in mRNA biogenesis including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation. During mRNA export, the nuclear cap-binding protein complex recruits ribosomes to begin the pioneer round of translation. When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional heterodimer and composed of Cbc1/Cbc2 in yeast and CBP20/CBP80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBP80 consists of 757 amino acid residues. Its secondary structure contains approximately sixty percent of helical and one percent of beta sheet in the strand. The small subunit, CBP20 has 98 amino acid residues. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand. Human nuclear cap-binding protein complex plays important role in the maturation of pre-mRNA and in uracil-rich small nuclear RNA.

<span class="mw-page-title-main">Cap binding complex</span> Formation on 5 ends of mRNAs

The 5' cap of eukaryotic messenger RNA is bound at all times by various cap-binding complexes (CBCs).

<span class="mw-page-title-main">NSP3 (rotavirus)</span>

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

<span class="mw-page-title-main">EIF4E</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">EIF4G2</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 2 is a protein that in humans is encoded by the EIF4G2 gene.

<span class="mw-page-title-main">Eukaryotic translation initiation factor 4 gamma 1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">EIF4A1</span> 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.

<span class="mw-page-title-main">EIF1</span> Protein-coding gene in the species Homo sapiens

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 an 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.

The 43S preinitiation complex is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3, and the eIF2-Met-tRNAiMet-GTP ternary complex (eIF2-TC).

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. 115 (6). Elsevier BV: 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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