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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.^[1]^[2] 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.^[2]

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.^[2]

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.^[3]

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.^[2] 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 (PIC) via eIF4A's RNA helicase activity.^[2]

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.^[2] Interactions between eIF4G and PABP are thought to mediate the circularization of mRNA particles.^[4]

Subunit	MW (kDa)^[A]	Isoforms	Key Features
eIF4A	46	eIF4A1, eIF4A2, eIF4A3	DEAD-box RNA helicase. Binds mRNA, eIF4G, eIF4B, eIF4H, and PDCD4.
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.

Regulation

The eIF4E subunit of eIF4F is an important target of mTOR signaling through the eIF4E binding protein (4E-BP).^[2] Phosphorylation of 4E-BPs by mTOR prevents their binding to eIF4E, freeing eIF4E to bind eIF4G and participate in translation initiation.^[2]

References

^ Aitken, Colin E.; Lorsch, Jon R. (2012). "A mechanistic overview of translation initiation in eukaryotes". Nat. Struct. Mol. Biol. 19 (6): 568–576. PMID 22664984. doi:10.1038/nsmb.2303. Retrieved 20 February 2016.
^ ^a ^b ^c ^d ^e ^f ^g ^h Merrick, William C. (2015). "eIF4F: A Retrospective". J. Biol. Chem. 290 (40): 24091–24099. PMID 26324716. doi:10.1074/jbc.R115.675280. Retrieved 27 February 2016.
^ Fraser, Christopher S. (2015). "Quantitative studies of mRNA recruitment to the eukaryotic ribosome". Biochimie. 114: 58–71. PMC 4458453 . PMID 25742741. doi:10.1016/j.biochi.2015.02.017. Retrieved 6 March 2016.
^ Wells, Sandra E.; Hillner, Paul E.; Vale, Ronald D.; Sachs, Alan B. (1998). "Circularization of mRNA by Eukaryotic Translation Initiation Factors". Mol. Cell. 2 (1): 135–140. PMID 9702200. doi:10.1016/S1097-2765(00)80122-7. Retrieved 29 February 2016.

English Journal

Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

Liu T, Nair SJ, Lescarbeau A, Belani J, Peluso S, Conley J, Tillotson B, O'Hearn P, Smith S, Slocum K, West K, Helble J, Douglas M, Bahadoor A, Ali J, McGovern K, Fritz C, Palombella V, Wylie A, Castro A, Tremblay M.AbstractMis-regulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor drug-like properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C-6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e. complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compound 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to silvestrol.
Journal of medicinal chemistry.J Med Chem.2012 Oct 1. [Epub ahead of print]
Mis-regulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical
PMID 23025805

The eIF4E repressor protein 4E-BP2 is merely truncated, despite 4E-BP1 degradation in the porcine uterine tissue during implantation.

Wollenhaupt K, Brüssow KP, Albrecht D, Tomek W.SourceLeibniz Institute for Farm Animal Biology, Reproductive Biology, Dummerstorf, Germany.
Molecular reproduction and development.Mol Reprod Dev.2012 Sep 11. doi: 10.1002/mrd.22108. [Epub ahead of print]
Recently, we identified an N-terminally truncated form of the mRNA cap binding protein eIF4E in the porcine luminal epithelium during implantation. EIF4E truncation is accompanied by degradation of the eIF4E-repressor protein 4E-BP1. In this study, we investigated whether or not the other members of
PMID 22968905

Japanese Journal

Poly(A)-binding protein facilitates translation of an uncapped/nonpolyadenylated viral RNA by binding to the 3' untranslated region.

Iwakawa Hiro-Oki,Tajima Yuri,Taniguchi Takako,Kaido Masanori,Mise Kazuyuki,Tomari Yukihide,Taniguchi Hisaaki,Okuno Tetsuro
Journal of virology 86(15), 7836-7849, 2012-08
… We also found that both the ARS and 3'CITE are important for the recruitment of the plant eIF4F and eIFiso4F factors to the 3' UTR and of the 40S ribosomal subunit to the viral mRNA. …
NAID 120004873608

Isolation and functional characterization of eIF4F components and poly(A)-binding protein from Plasmodium falciparum

TUTEJA Renu,PRADHAN Arun
Parasitology international : official journal of the Japanese Society of Parasitology 58(4), 481-485, 2009-12-01
NAID 10027671106

MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F

MATHONNET G
Science 317, 1764-1767, 2007
NAID 80018207773

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★リンクテーブル★

リンク元	「真核生物翻訳開始因子4F」「eukaryotic initiation factor-4F」「eukaryotic translation initiation factor 4F」
関連記事	「eIF」