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eIF4A

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eukaryotic translation initiation factor 4A, isoform 1
Identifiers
SymbolEIF4A1
Alt. symbolsEIF4A
NCBI gene1973
HGNC3282
OMIM602641
RefSeqNM_001416
UniProtP60842
Other data
LocusChr. 17 p13
Search for
StructuresSwiss-model
DomainsInterPro
eukaryotic translation initiation factor 4A, isoform 2
Identifiers
SymbolEIF4A2
Alt. symbolsEIF4F
NCBI gene1974
HGNC3284
OMIM601102
RefSeqNM_001967
UniProtQ14240
Other data
EC number3.6.1.1
LocusChr. 3 q28
Search for
StructuresSwiss-model
DomainsInterPro
eukaryotic translation initiation factor 4A, isoform 3
Identifiers
SymbolEIF4A3
Alt. symbolsDDX48
NCBI gene9775
HGNC18683
OMIM608546
RefSeqNM_014740
UniProtP38919
Other data
LocusChr. 17 q25.3
Search for
StructuresSwiss-model
DomainsInterPro

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.[1][2]

Background

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.[3] Human translational control is of increasing research interest as it has connotations in a range of diseases.[4] 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,[5] rodent brain[6] and rabbit reticulocytes.[7] 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".[8] 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.

Function

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.

Mechanism

The repertoire of compounds involved in eukaryotic translation consists of initiation factor classes 1 – 6;[9] 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.[10] 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).[11] 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.[12] Once bound to the 5’ cap of mRNA, this 48S complex then searches for the (usually) AUG start codon and translation begins.

Genes

In humans, the gene encoding eIF4A isoform I has a transcript length of 1741bp, contains 11 exons, and is located on chromosome 17.[13][14] The genes for human isoforms II and III reside on chromosomes 3[15] and 17[16][17] respectively.

Proteins

The 407 residue,[15] 46 kDa,[18] 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.[19] Crystallographic analysis of yeast eIF4A carried out by Carruthers et al. (2000)[20] 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.[21]

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.[22] 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.[23]

See also

References

  1. ^ Rogers GW, Komar AA, Merrick WC (2002). "eIF4A: the godfather of the DEAD box helicases". Progress in Nucleic Acid Research and Molecular Biology. 72: 307–31. doi:10.1016/S0079-6603(02)72073-4. PMID 12206455.
  2. ^ Schütz P, Bumann M, Oberholzer AE, Bieniossek C, Trachsel H, Altmann M, Baumann U (Jul 2008). "Crystal structure of the yeast eIF4A-eIF4G complex: an RNA-helicase controlled by protein-protein interactions". Proceedings of the National Academy of Sciences of the United States of America. 105 (28): 9564–9. doi:10.1073/pnas.0800418105. PMC 2474498. PMID 18606994.
  3. ^ Gingras AC, Raught B, Sonenberg N (June 1999). "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation". Annual Review of Biochemistry. 68 (1): 913–63. doi:10.1146/annurev.biochem.68.1.913. PMID 10872469.
  4. ^ Hollams EM, Giles KM, Thomson AM, Leedman PJ (Oct 2002). "MRNA stability and the control of gene expression: implications for human disease". Neurochemical Research. 27 (10): 957–80. doi:10.1023/A:1020992418511. PMID 12462398.
  5. ^ Castañeda M (Apr 1969). "The activity of ribosomes of sea urchin eggs in response to fertilization". Biochimica et Biophysica Acta. 179 (2): 381–8. doi:10.1016/0005-2787(69)90046-X. PMID 5814313.
  6. ^ Vargas R, Castañeda M (Feb 1983). "Age-dependent decrease in the activity of protein-synthesis initiation factors in rat brain". Mechanisms of Ageing and Development. 21 (2): 183–91. doi:10.1016/0047-6374(83)90073-8. PMID 6865504.
  7. ^ Li W, Belsham GJ, Proud CG (Aug 2001). "Eukaryotic initiation factors 4A (eIF4A) and 4G (eIF4G) mutually interact in a 1:1 ratio in vivo". The Journal of Biological Chemistry. 276 (31): 29111–5. doi:10.1074/jbc.C100284200. PMID 11408474.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Jacob F, Monod J (Jun 1961). "Genetic regulatory mechanisms in the synthesis of proteins". Journal of Molecular Biology. 3: 318–56. doi:10.1016/S0022-2836(61)80072-7. PMID 13718526.
  9. ^ Hershey JW Merrick WC (2000). "Pathway and mechanism of initiation of protein synthesis". In Mathews M, Sonenberg N, Hershey JW (eds.). Translational control of gene expression. Plainview, N.Y: Cold Spring Harbor Laboratory Press. pp. 33–88. ISBN 0-87969-568-4.
  10. ^ Yao N, Hesson T, Cable M, Hong Z, Kwong AD, Le HV, Weber PC (Jun 1997). "Structure of the hepatitis C virus RNA helicase domain". Nature Structural Biology. 4 (6): 463–7. doi:10.1038/nsb0697-463. PMID 9187654.
  11. ^ Korneeva NL, First EA, Benoit CA, Rhoads RE (Jan 2005). "Interaction between the NH2-terminal domain of eIF4A and the central domain of eIF4G modulates RNA-stimulated ATPase activity". The Journal of Biological Chemistry. 280 (3): 1872–81. doi:10.1074/jbc.M406168200. PMID 15528191.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Bi X, Ren J, Goss DJ (May 2000). "Wheat germ translation initiation factor eIF4B affects eIF4A and eIFiso4F helicase activity by increasing the ATP binding affinity of eIF4A". Biochemistry. 39 (19): 5758–65. doi:10.1021/bi992322p. PMID 10801326.
  13. ^ Kim NS, Kato T, Abe N, Kato S (Apr 1993). "Nucleotide sequence of human cDNA encoding eukaryotic initiation factor 4AI". Nucleic Acids Research. 21 (8): 2012. doi:10.1093/nar/21.8.2012. PMC 309447. PMID 8493113.
  14. ^ Jones E, Quinn CM, See CG, Montgomery DS, Ford MJ, Kölble K, Gordon S, Greaves DR (Oct 1998). "The linked human elongation initiation factor 4A1 (EIF4A1) and CD68 genes map to chromosome 17p13". Genomics. 53 (2): 248–50. doi:10.1006/geno.1998.5515. PMID 9790779.
  15. ^ a b Sudo K, Takahashi E, Nakamura Y (1995). "Isolation and mapping of the human EIF4A2 gene homologous to the murine protein synthesis initiation factor 4A-II gene Eif4a2". Cytogenetics and Cell Genetics. 71 (4): 385–8. doi:10.1159/000134145. PMID 8521730.
  16. ^ Holzmann K, Gerner C, Pöltl A, Schäfer R, Obrist P, Ensinger C, Grimm R, Sauermann G (Jan 2000). "A human common nuclear matrix protein homologous to eukaryotic translation initiation factor 4A". Biochemical and Biophysical Research Communications. 267 (1): 339–44. doi:10.1006/bbrc.1999.1973. PMID 10623621.
  17. ^ Chan CC, Dostie J, Diem MD, Feng W, Mann M, Rappsilber J, Dreyfuss G (Feb 2004). "eIF4A3 is a novel component of the exon junction complex". Rna. 10 (2): 200–9. doi:10.1261/rna.5230104. PMC 1370532. PMID 14730019.
  18. ^ Belsham GJ, McInerney GM, Ross-Smith N (Jan 2000). "Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells". Journal of Virology. 74 (1): 272–80. doi:10.1128/JVI.74.1.272-280.2000. PMC 111537. PMID 10590115.
  19. ^ Pause A, Sonenberg N (Jul 1992). "Mutational analysis of a DEAD box RNA helicase: the mammalian translation initiation factor eIF-4A". The EMBO Journal. 11 (7): 2643–54. PMC 556740. PMID 1378397.
  20. ^ Caruthers JM, Johnson ER, McKay DB (Nov 2000). "Crystal structure of yeast initiation factor 4A, a DEAD-box RNA helicase". Proceedings of the National Academy of Sciences of the United States of America. 97 (24): 13080–5. doi:10.1073/pnas.97.24.13080. PMC 27181. PMID 11087862.
  21. ^ Lin D, Pestova TV, Hellen CU, Tiedge H (May 2008). "Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism". Molecular and Cellular Biology. 28 (9): 3008–19. doi:10.1128/MCB.01800-07. PMC 2293081. PMID 18316401.
  22. ^ Yoder-Hill J, Pause A, Sonenberg N, Merrick WC (Mar 1993). "The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF-4A". The Journal of Biological Chemistry. 268 (8): 5566–73. PMID 8449919.
  23. ^ Bordeleau ME, Matthews J, Wojnar JM, Lindqvist L, Novac O, Jankowsky E, Sonenberg N, Northcote P, Teesdale-Spittle P, Pelletier J (Jul 2005). "Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation". Proceedings of the National Academy of Sciences of the United States of America. 102 (30): 10460–5. doi:10.1073/pnas.0504249102. PMC 1176247. PMID 16030146.
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