eIF4A

The mechanisms governing the basic subsistence of eukaryotic cells are immensely complex; it is therefore unsurprising that regulation occurs at a number of stages of protein synthesis – the regulation of translation has become a well-studied field.{{cite journal | vauthors = Gingras AC, Raught B, Sonenberg N | title = eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation | journal = Annual Review of Biochemistry | volume = 68 | issue = 1 | pages = 913–63 | date = June 1999 | pmid = 10872469 | doi = 10.1146/annurev.biochem.68.1.913 }} Human translational control is of increasing research interest as it has connotations in a range of diseases.{{cite journal | vauthors = Hollams EM, Giles KM, Thomson AM, Leedman PJ | title = MRNA stability and the control of gene expression: implications for human disease | journal = Neurochemical Research | volume = 27 | issue = 10 | pages = 957–80 | date = Oct 2002 | pmid = 12462398 | doi = 10.1023/A:1020992418511 | s2cid = 10737331 }} Orthologs of many of the factors involved in human translation are shared by a range of eukaryotic organisms; some of which are used as model systems for the investigation of translation initiation and elongation, for example: sea urchin eggs upon fertilization,{{cite journal | vauthors = Castañeda M | title = The activity of ribosomes of sea urchin eggs in response to fertilization | journal = Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis | volume = 179 | issue = 2 | pages = 381–8 | date = Apr 1969 | pmid = 5814313 | doi = 10.1016/0005-2787(69)90046-X }} rodent brain{{cite journal | vauthors = Vargas R, Castañeda M | title = Age-dependent decrease in the activity of protein-synthesis initiation factors in rat brain | journal = Mechanisms of Ageing and Development | volume = 21 | issue = 2 | pages = 183–91 | date = Feb 1983 | pmid = 6865504 | doi = 10.1016/0047-6374(83)90073-8 | s2cid = 24826675 }} and rabbit reticulocytes.{{cite journal | vauthors = Li W, Belsham GJ, Proud CG | title = Eukaryotic initiation factors 4A (eIF4A) and 4G (eIF4G) mutually interact in a 1:1 ratio in vivo | journal = The Journal of Biological Chemistry | volume = 276 | issue = 31 | pages = 29111–5 | date = Aug 2001 | pmid = 11408474 | doi = 10.1074/jbc.C100284200 | doi-access = free }} Monod and Jacob were among the first to propose that "the synthesis of individual proteins may be provoked or suppressed within a cell, under the influence of specific external agents, and the relative rates at which different proteins may be profoundly altered, depending upon external conditions".{{cite journal | vauthors = Jacob F, Monod J | title = Genetic regulatory mechanisms in the synthesis of proteins | journal = Journal of Molecular Biology | volume = 3 | issue = 3| pages = 318–56 | date = Jun 1961 | pmid = 13718526 | doi = 10.1016/S0022-2836(61)80072-7 | s2cid = 19804795 }} Almost half a century after the flurry of postulations arising from the revelation of the central dogma of molecular biology, of which the preceding supposition by Monod and Jacob is an example; contemporary researchers still have much to learn about the modulation of genetic expression. Synthesis of protein from mature messenger RNA in eukaryotes is divided into translation initiation, elongation, and termination of these stages; the initiation of translation is the rate limiting step. Within the process of translation initiation; the bottleneck occurs shortly before the ribosome binds to the 5’ m7GTP facilitated by a number of proteins; it is at this stage that constrictions born of stress, amino acid starvation etc. take effect.

Eukaryotic initiation factor complex 2 (eIF2) forms a ternary complex with GTP and the initiator Met-tRNA – this process is regulated by guanine nucleotide exchange and phosphorylation and serves as the main regulatory element of the bottleneck of gene expression. Before translation can progress to the elongation stage, a number of initiation factors must facilitate the synergy of the ribosome and the mRNA and ensure that the 5’ UTR of the mRNA is sufficiently devoid of secondary structure. Binding in this way is facilitated by group 4 eukaryotic initiation factors; eIF4F has implications in the normal regulation of translation as well as the transformation and progression of cancerous cells; as such, it represents an interesting field of research.

The repertoire of compounds involved in eukaryotic translation consists of initiation factor classes 1 – 6;{{cite book | author = Hershey JW Merrick WC |veditors=Mathews M, Sonenberg N, Hershey JW | title = Translational control of gene expression | publisher = Cold Spring Harbor Laboratory Press | location = Plainview, N.Y | year = 2000 | chapter = Pathway and mechanism of initiation of protein synthesis | pages = 33–88 | isbn = 978-0-87969-568-2 }} eIF4F is responsible for the binding of capped mRNA to the 40S ribosomal subunit via eIF3. The mRNA cap is bound by eIF4E (25 kDa), eIF4G (185 kDa) acts as a scaffold for the complex whilst the ATP-dependent RNA helicase eIF4A (46 kDa) processes the secondary structure of the mRNA 5’ UTR to render it more conducive to ribosomal binding and subsequent translation.{{cite journal | vauthors = Yao N, Hesson T, Cable M, Hong Z, Kwong AD, Le HV, Weber PC | title = Structure of the hepatitis C virus RNA helicase domain | journal = Nature Structural Biology | volume = 4 | issue = 6 | pages = 463–7 | date = Jun 1997 | pmid = 9187654 | doi = 10.1038/nsb0697-463 | s2cid = 12434586 }} Together these three proteins are referred to as eIF4F. For maximal activity; eIF4A also requires eIF4B (80 kDa), which itself is enhanced by eIF4H (25 kDa).{{cite journal | vauthors = Korneeva NL, First EA, Benoit CA, Rhoads RE | title = Interaction between the NH2-terminal domain of eIF4A and the central domain of eIF4G modulates RNA-stimulated ATPase activity | journal = The Journal of Biological Chemistry | volume = 280 | issue = 3 | pages = 1872–81 | date = Jan 2005 | pmid = 15528191 | doi = 10.1074/jbc.M406168200 | doi-access = free }} A study conducted by Bi et al. in wheat germ seemed to indicate that eIF4A has a higher binding affinity for ADP than ATP except in the presence of eIF4B, which increased the ATP binding affinity tenfold without affecting ADP affinity.{{cite journal | vauthors = Bi X, Ren J, Goss DJ | title = Wheat germ translation initiation factor eIF4B affects eIF4A and eIFiso4F helicase activity by increasing the ATP binding affinity of eIF4A | journal = Biochemistry | volume = 39 | issue = 19 | pages = 5758–65 | date = May 2000 | pmid = 10801326 | doi = 10.1021/bi992322p }} Once bound to the 5’ cap of mRNA, this 48S complex then searches for the (usually) AUG start codon and translation begins.

In humans, the gene encoding eIF4A isoform I has a transcript length of 1741bp, contains 11 exons, and is located on chromosome 17.{{cite journal | vauthors = Kim NS, Kato T, Abe N, Kato S | title = Nucleotide sequence of human cDNA encoding eukaryotic initiation factor 4AI | journal = Nucleic Acids Research | volume = 21 | issue = 8 | pages = 2012 | date = Apr 1993 | pmid = 8493113 | pmc = 309447 | doi = 10.1093/nar/21.8.2012 }}{{cite journal | vauthors = Jones E, Quinn CM, See CG, Montgomery DS, Ford MJ, Kölble K, Gordon S, Greaves DR | title = The linked human elongation initiation factor 4A1 (EIF4A1) and CD68 genes map to chromosome 17p13 | journal = Genomics | volume = 53 | issue = 2 | pages = 248–50 | date = Oct 1998 | pmid = 9790779 | doi = 10.1006/geno.1998.5515 }} The genes for human isoforms II and III reside on chromosomes 3{{cite journal | vauthors = Sudo K, Takahashi E, Nakamura Y | title = Isolation and mapping of the human EIF4A2 gene homologous to the murine protein synthesis initiation factor 4A-II gene Eif4a2 | journal = Cytogenetics and Cell Genetics | volume = 71 | issue = 4 | pages = 385–8 | year = 1995 | pmid = 8521730 | doi = 10.1159/000134145 }} and 17{{cite journal | vauthors = Holzmann K, Gerner C, Pöltl A, Schäfer R, Obrist P, Ensinger C, Grimm R, Sauermann G | title = A human common nuclear matrix protein homologous to eukaryotic translation initiation factor 4A | journal = Biochemical and Biophysical Research Communications | volume = 267 | issue = 1 | pages = 339–44 | date = Jan 2000 | pmid = 10623621 | doi = 10.1006/bbrc.1999.1973 }}{{cite journal | vauthors = Chan CC, Dostie J, Diem MD, Feng W, Mann M, Rappsilber J, Dreyfuss G | title = eIF4A3 is a novel component of the exon junction complex | journal = RNA | volume = 10 | issue = 2 | pages = 200–9 | date = Feb 2004 | pmid = 14730019 | pmc = 1370532 | doi = 10.1261/rna.5230104 }} respectively.

The 407 residue, 46 kDa,{{cite journal | vauthors = Belsham GJ, McInerney GM, Ross-Smith N | title = Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells | journal = Journal of Virology | volume = 74 | issue = 1 | pages = 272–80 | date = Jan 2000 | pmid = 10590115 | pmc = 111537 | doi = 10.1128/JVI.74.1.272-280.2000 }} protein eIF4A is the prototypical member of the DEAD box helicase family, so-called due to their conserved four-residue D-E-A-D sequence. This family of helicases is found in a range of prokaryotic and eukaryotic organisms including humans, wherein they catalyse a variety of processes including embryogenesis and RNA splicing as well as translation initiation.{{cite journal | vauthors = Pause A, Sonenberg N | title = Mutational analysis of a DEAD box RNA helicase: the mammalian translation initiation factor eIF-4A | journal = The EMBO Journal | volume = 11 | issue = 7 | pages = 2643–54 | date = Jul 1992 | pmid = 1378397 | pmc = 556740 | doi = 10.1002/j.1460-2075.1992.tb05330.x}} Crystallographic analysis of yeast eIF4A carried out by Carruthers et al. (2000){{cite journal | vauthors = Caruthers JM, Johnson ER, McKay DB | title = Crystal structure of yeast initiation factor 4A, a DEAD-box RNA helicase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 24 | pages = 13080–5 | date = Nov 2000 | pmid = 11087862 | pmc = 27181 | doi = 10.1073/pnas.97.24.13080 | bibcode = 2000PNAS...9713080C | doi-access = free }} revealed that the molecule is approximately 80 Å in length and has a “dumbbell” shape where the proximal section represents an 11 residue (18 Å) linker postulated to confer a degree of flexibility and distension to the molecule in solution. eIF4A is an abundant cytoplasmic protein.{{cite journal | vauthors = Lin D, Pestova TV, Hellen CU, Tiedge H | author-link4 = Henri Tiedge | title = Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism | journal = Molecular and Cellular Biology | volume = 28 | issue = 9 | pages = 3008–19 | date = May 2008 | pmid = 18316401 | pmc = 2293081 | doi = 10.1128/MCB.01800-07 }}

Three isoforms of eIF4A exist; I and II share 95% amino acid similarity and have been found simultaneously in rabbit reticulocyte eIF4F in a ratio of 4:1, respectively.{{cite journal | vauthors = Yoder-Hill J, Pause A, Sonenberg N, Merrick WC | title = The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF-4A | journal = The Journal of Biological Chemistry | volume = 268 | issue = 8 | pages = 5566–73 | date = Mar 1993 | doi = 10.1016/S0021-9258(18)53358-5 | pmid = 8449919 | url = http://www.jbc.org/cgi/reprint/268/8/5566 | doi-access = free }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} The third isoform; eIF4A III, which shares only 65% similarity to the other isoforms is believed to be a core component of the exon junction complex involved in pre-mRNA splicing.{{cite journal | vauthors = Bordeleau ME, Matthews J, Wojnar JM, Lindqvist L, Novac O, Jankowsky E, Sonenberg N, Northcote P, Teesdale-Spittle P, Pelletier J | title = Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 30 | pages = 10460–5 | date = Jul 2005 | pmid = 16030146 | pmc = 1176247 | doi = 10.1073/pnas.0504249102 | bibcode = 2005PNAS..10210460B | doi-access = free }}

• Eukaryotic initiation factor
• Eukaryotic initiation factor 4F (eIF4F)
• Hippuristanol
• Rocaglamide

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Category:Human proteins