Eukaryotic initiation factor

eIF1 and eIF1A both bind to the 40S ribosome subunit-mRNA complex. Together they induce an "open" conformation of the mRNA binding channel, which is crucial for scanning, tRNA delivery, and start codon recognition.{{cite journal | vauthors = Passmore LA, Schmeing TM, Maag D, Applefield DJ, Acker MG, Algire MA, Lorsch JR, Ramakrishnan V | title = The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome | journal = Molecular Cell | volume = 26 | issue = 1 | pages = 41–50 | date = April 2007 | pmid = 17434125 | doi = 10.1016/j.molcel.2007.03.018 | doi-access = free }} In particular, eIF1 dissociation from the 40S subunit is considered to be a key step in start codon recognition.{{cite journal | vauthors = Cheung YN, Maag D, Mitchell SF, Fekete CA, Algire MA, Takacs JE, Shirokikh N, Pestova T, Lorsch JR, Hinnebusch AG | title = Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo | journal = Genes & Development | volume = 21 | issue = 10 | pages = 1217–30 | date = May 2007 | pmid = 17504939 | pmc = 1865493 | doi = 10.1101/gad.1528307 }}

eIF1 and eIF1A are small proteins (13 and 16 kDa, respectively in humans) and are both components of the 43S PIC. eIF1 binds near the ribosomal P-site, while eIF1A binds near the A-site, in a manner similar to the structurally and functionally related bacterial counterparts IF3 and IF1, respectively.{{cite journal | vauthors = Fraser CS | title = Quantitative studies of mRNA recruitment to the eukaryotic ribosome | journal = Biochimie | volume = 114 | pages = 58–71 | date = July 2015 | pmid = 25742741 | pmc = 4458453 | doi = 10.1016/j.biochi.2015.02.017 }}

{{main article|eIF2}}

eIF2 is the main protein complex responsible for delivering the initiator tRNA to the P-site of the preinitiation complex, as a ternary complex containing Met-tRNA_i^Met and GTP (the eIF2-TC). eIF2 has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs used for elongation of the polypeptide chain. The eIF2 ternary complex remains bound to the P-site while the mRNA attaches to the 40s ribosome and the complex begins to scan the mRNA. Once the AUG start codon is recognized and located in the P-site, eIF5 stimulates the hydrolysis of eIF2-GTP, effectively switching it to the GDP-bound form via gated phosphate release.{{cite journal | vauthors = Aitken CE, Lorsch JR | title = A mechanistic overview of translation initiation in eukaryotes | journal = Nature Structural & Molecular Biology | volume = 19 | issue = 6 | pages = 568–76 | date = June 2012 | pmid = 22664984 | doi = 10.1038/nsmb.2303 | s2cid = 9201095 }} The hydrolysis of eIF2-GTP provides the conformational change to change the scanning complex into the 48S Initiation complex with the initiator tRNA-Met anticodon base paired to the AUG. After the initiation complex is formed the 60s subunit joins and eIF2 along with most of the initiation factors dissociate from the complex allowing the 60S subunit to bind. eIF1A and eIF5B-GTP remain bound to one another in the A site and must be hydrolyzed to be released and properly initiate elongation.{{Cite book|vauthors=Lodish H, Berk A, Kaiser CA, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC|title=Molecular Cell Biology|edition=8th|language=en|isbn=978-1-4641-8339-3|lccn=2015957295|year=2016|publisher=W. H. Freeman and Company|location=New York}}{{rp|191-192}}

eIF2 has three subunits, eIF2-α, β, and γ. The former α-subunit is a target of regulatory phosphorylation and is of particular importance for cells that may need to turn off protein synthesis globally as a response to cell signaling events. When phosphorylated, it sequesters eIF2B (not to be confused with eIF2β), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed. One example of this is the eIF2α-induced translation repression that occurs in reticulocytes when starved for iron. In the case of viral infection, protein kinase R (PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.

The proteins eIF2A and eIF2D are both technically named 'eIF2' but neither are part of the eIF2 heterotrimer and they seem to play unique functions in translation. Instead, they appear to be involved in specialized pathways, such as 'eIF2-independent' translation initiation or re-initiation, respectively.

{{main article|eIF3}}

eIF3 independently binds the 40S ribosomal subunit, multiple initiation factors, and cellular and viral mRNA.{{cite journal | vauthors = Hinnebusch AG | title = eIF3: a versatile scaffold for translation initiation complexes | language = en | journal = Trends in Biochemical Sciences | volume = 31 | issue = 10 | pages = 553–62 | date = October 2006 | pmid = 16920360 | doi = 10.1016/j.tibs.2006.08.005 }}

In mammals, eIF3 is the largest initiation factor, made up of 13 subunits (a-m). It has a molecular weight of ~800 kDa and controls the assembly of the 40S ribosomal subunit on mRNA that have a 5' cap or an IRES. eIF3 may use the eIF4F complex, or alternatively during internal initiation, an IRES, to position the mRNA strand near the exit site of the 40S ribosomal subunit, thus promoting the assembly of a functional pre-initiation complex.

In many human cancers, eIF3 subunits are overexpressed (subunits a, b, c, h, i, and m) and underexpressed (subunits e and f).{{cite journal | vauthors = Hershey JW | title = The role of eIF3 and its individual subunits in cancer | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1849 | issue = 7 | pages = 792–800 | date = July 2015 | pmid = 25450521 | doi = 10.1016/j.bbagrm.2014.10.005 }} One potential mechanism to explain this disregulation comes from the finding that eIF3 binds a specific set of cell proliferation regulator mRNA transcripts and regulates their translation.{{cite journal | vauthors = Lee AS, Kranzusch PJ, Cate JH | title = eIF3 targets cell-proliferation messenger RNAs for translational activation or repression | language = en | journal = Nature | volume = 522 | issue = 7554 | pages = 111–4 | date = June 2015 | pmid = 25849773 | pmc = 4603833 | doi = 10.1038/nature14267 | bibcode = 2015Natur.522..111L }} eIF3 also mediates cellular signaling through S6K1 and mTOR/Raptor to effect translational regulation.{{cite journal | vauthors = Holz MK, Ballif BA, Gygi SP, Blenis J | title = mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events | journal = Cell | volume = 123 | issue = 4 | pages = 569–80 | date = November 2005 | pmid = 16286006 | doi = 10.1016/j.cell.2005.10.024 | doi-access = free }}

{{main article|eIF4F}}

The eIF4F complex is composed of three subunits: eIF4A, eIF4E, and eIF4G. Each subunit has multiple human isoforms and there exist additional eIF4 proteins: eIF4B and eIF4H.

eIF4G is a 175.5-kDa scaffolding protein that interacts with eIF3 and the Poly(A)-binding protein (PABP), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds PABP, which binds the poly(A) tail, potentially circularizing and activating the bound mRNA. eIF4A{{spaced ndash}}a DEAD box RNA helicase{{spaced ndash}}is important for resolving mRNA secondary structures.

eIF4B contains two RNA-binding domains{{spaced ndash}}one non-specifically interacts with mRNA, whereas the second specifically binds the 18S portion of the small ribosomal subunit. It acts as an anchor, as well as a critical co-factor for eIF4A. It is also a substrate of S6K, and when phosphorylated, it promotes the formation of the pre-initiation complex. In vertebrates, eIF4H is an additional initiation factor with similar function to eIF4B.

eIF5 is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2.

eIF5A is the eukaryotic homolog of EF-P. It helps with elongation and also plays a role in termination. EIF5A contains the unusual amino acid hypusine.{{cite journal |last1=Schuller |first1=AP |last2=Wu |first2=CC |last3=Dever |first3=TE |last4=Buskirk |first4=AR |last5=Green |first5=R |title=eIF5A Functions Globally in Translation Elongation and Termination. |journal=Molecular Cell |date=20 April 2017 |volume=66 |issue=2 |pages=194–205.e5 |doi=10.1016/j.molcel.2017.03.003 |pmid=28392174|pmc=5414311 }}

eIF5B is a GTPase, and is involved in assembly of the full ribosome. It is the functional eukaryotic analog of bacterial IF2.{{cite journal | vauthors = Allen GS, Frank J | title = Structural insights on the translation initiation complex: ghosts of a universal initiation complex | journal = Molecular Microbiology | volume = 63 | issue = 4 | pages = 941–50 | date = February 2007 | pmid = 17238926 | doi = 10.1111/j.1365-2958.2006.05574.x | doi-access = free }}

{{main article| eIF6}}

eIF6 performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit.

• Eukaryotic translation
• Ded1/DDX3
• DHX29

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• {{cite journal | vauthors = Fraser CS, Doudna JA | title = Structural and mechanistic insights into hepatitis C viral translation initiation | journal = Nature Reviews. Microbiology | volume = 5 | issue = 1 | pages = 29–38 | date = January 2007 | pmid = 17128284 | doi = 10.1038/nrmicro1558 | s2cid = 638721 }}
• {{cite journal | vauthors = Malys N, McCarthy JE | title = Translation initiation: variations in the mechanism can be anticipated | journal = Cellular and Molecular Life Sciences | volume = 68 | issue = 6 | pages = 991–1003 | date = March 2011 | pmid = 21076851 | doi = 10.1007/s00018-010-0588-z | s2cid = 31720000 | pmc = 11115079 }}

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• {{MeshName|Eukaryotic+Initiation+Factors}}

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Category:Helicases

Category:Molecular biology

Category:Protein biosynthesis

Category:Gene expression