EIF4A

Last updated
eukaryotic translation initiation factor 4A, isoform 1
Identifiers
Symbol EIF4A1
Alt. symbolsEIF4A
NCBI gene 1973
HGNC 3282
OMIM 602641
RefSeq NM_001416
UniProt P60842
Other data
Locus Chr. 17 p13
eukaryotic translation initiation factor 4A, isoform 2
Identifiers
Symbol EIF4A2
Alt. symbolsEIF4F
NCBI gene 1974
HGNC 3284
OMIM 601102
RefSeq NM_001967
UniProt Q14240
Other data
EC number 3.6.1.1
Locus Chr. 3 q28
eukaryotic translation initiation factor 4A, isoform 3
Identifiers
Symbol EIF4A3
Alt. symbolsDDX48
NCBI gene 9775
HGNC 18683
OMIM 608546
RefSeq NM_014740
UniProt P38919
Other data
Locus Chr. 17 q25.3

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]

Contents

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

Related Research Articles

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

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.

PABPC1 Protein-coding gene in the species Homo sapiens

Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport into and out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.

EIF4E

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

EIF4G2

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

Eukaryotic translation initiation factor 4 gamma 1

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

EIF6

Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene.

EIF4G3 Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 3 is a protein that in humans is encoded by the EIF4G3 gene. The gene encodes a protein that functions in translation by aiding the assembly of the ribosome onto the messenger RNA template. Confusingly, this protein is usually referred to as eIF4GII, as although EIF4G3 is the third gene that is similar to eukaryotic translation initiation factor 4 gamma, the second isoform EIF4G2 is not an active translation initiation factor.

EIF2S3 Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 3 (eIF2γ) is a protein that in humans is encoded by the EIF2S3 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.

EIF4B

Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.

EIF4A3 Protein-coding gene in the species Homo sapiens

Eukaryotic initiation factor 4A-III is a protein that in humans is encoded by the EIF4A3 gene.

EIF2A

Eukaryotic translation initiation factor 2A (eIF2A) is a protein that in humans is encoded by the EIF2A gene. The eIF2A protein is not to be confused with eIF2α, a subunit of the heterotrimeric eIF2 complex. Instead, eIF2A functions by a separate mechanism in eukaryotic translation.

EIF1AX Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the EIF1AX gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs.

EIF3D

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a protein that in humans is encoded by the EIF3D gene.

<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 a 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.

Translation regulation by 5′ transcript leader cis-elements

Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.

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. Vol. 72. pp. 307–31. doi:10.1016/S0079-6603(02)72073-4. ISBN   9780125400725. 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. Bibcode:2008PNAS..105.9564S. 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. S2CID   10737331.
  5. ↑ Castañeda M (Apr 1969). "The activity of ribosomes of sea urchin eggs in response to fertilization". Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis. 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. S2CID   24826675.
  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.
  8. ↑ Jacob F, Monod J (Jun 1961). "Genetic regulatory mechanisms in the synthesis of proteins". Journal of Molecular Biology. 3 (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   978-0-87969-568-2.
  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. S2CID   12434586.
  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.
  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. 1 2 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. doi:10.1002/j.1460-2075.1992.tb05330.x. 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. Bibcode:2000PNAS...9713080C. 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. doi: 10.1016/S0021-9258(18)53358-5 . 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. Bibcode:2005PNAS..10210460B. doi: 10.1073/pnas.0504249102 . PMC   1176247 . PMID   16030146.
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