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{{Short description|Protein family}}
{{lowercase}}
{{infobox protein
| Name = [[EIF4A1|eukaryotic translation initiation factor 4A, isoform 1]]
| caption =
| image =
| width =
| HGNCid = 3282
| Symbol = [[EIF4A1]]
| AltSymbols = EIF4A
| EntrezGene = 1973
| OMIM = 602641
| RefSeq = NM_001416
| UniProt = P60842
| PDB =
| ECnumber =
| Chromosome = 17
| Arm = p
| Band = 13
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[EIF4A2|eukaryotic translation initiation factor 4A, isoform 2]]
| caption =
| image =
| width =
| HGNCid = 3284
| Symbol = [[EIF4A2]]
| AltSymbols = EIF4F
| EntrezGene = 1974
| OMIM = 601102
| RefSeq = NM_001967
| UniProt = Q14240
| PDB =
| ECnumber = 3.6.1.1
| Chromosome = 3
| Arm = q
| Band = 28
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[EIF4A3|eukaryotic translation initiation factor 4A, isoform 3]]
| caption =
| image =
| width =
| HGNCid = 18683
| Symbol = [[EIF4A3]]
| AltSymbols = DDX48
| EntrezGene = 9775
| OMIM = 608546
| RefSeq = NM_014740
| UniProt = P38919
| PDB =
| ECnumber =
| Chromosome = 17
| Arm = q
| Band = 25.3
| LocusSupplementaryData =
}}
The '''eukaryotic initiation factor-4A''' ('''eIF4A''') family consists of 3 closely related [[protein]]s [[EIF4A1]], [[EIF4A2]], and [[EIF4A3]]. These factors are required for the binding of [[Messenger RNA|mRNA]] to [[40S]] [[ribosome|ribosomal]] subunits. In addition these proteins are [[helicase]]s that function to unwind double-stranded [[RNA]].<ref name="pmid12206455">{{cite book | vauthors = Rogers GW, Komar AA, Merrick WC | title = eIF4A: the godfather of the DEAD box helicases | journal = Progress in Nucleic Acid Research and Molecular Biology | volume = 72 | pages = 307–31 | year = 2002 | pmid = 12206455 | doi = 10.1016/S0079-6603(02)72073-4 | isbn = 9780125400725 }}</ref><ref name="pmid18606994">{{cite journal | vauthors = Schütz P, Bumann M, Oberholzer AE, Bieniossek C, Trachsel H, Altmann M, Baumann U | title = Crystal structure of the yeast eIF4A-eIF4G complex: an RNA-helicase controlled by protein-protein interactions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 28 | pages = 9564–9 | date = Jul 2008 | pmid = 18606994 | pmc = 2474498 | doi = 10.1073/pnas.0800418105 | bibcode = 2008PNAS..105.9564S | doi-access = free }}</ref>

== Background ==
The mechanisms governing the basic subsistence of [[Eukaryote|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.<ref name=gingras1999>{{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 }}</ref> Human translational control is of increasing research interest as it has connotations in a range of diseases.<ref name="Hollams_2002">{{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 }}</ref> 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 organism|model systems]] for the investigation of translation initiation and elongation, for example: [[sea urchin]] eggs upon fertilization,<ref name="Castaneda_1969">{{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 }}</ref> rodent brain<ref name="Vargas_1983">{{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 }}</ref> and rabbit reticulocytes.<ref name=li2001>{{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 }}</ref> 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".<ref name="pmid13718526">{{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 }}</ref> 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 [[Guanosine triphosphate|GTP]] and the initiator [[Methionine|Met]]-[[tRNA]] – this process is regulated by guanine nucleotide exchange and [[phosphorylation]] and serves as the main [[Regulatory sequence|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;<ref name="isbn0-87969-568-4">{{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 }}</ref> [[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.<ref name="pmid9187654">{{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 }}</ref> 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).<ref name="pmid15528191">{{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 }}</ref> A study conducted by Bi ''et al.'' in [[Cereal germ|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.<ref name="pmid10801326">{{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 }}</ref> 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 [[EIF4A1|eIF4A isoform I]] has a transcript length of 1741bp, contains 11 exons, and is located on chromosome 17.<ref name="pmid8493113">{{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 }}</ref><ref name="pmid9790779">{{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 }}</ref> The genes for human isoforms [[EIF4A2|II]] and [[EIF4A3|III]] reside on chromosomes 3<ref name="pmid8521730">{{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 }}</ref> and 17<ref name="pmid10623621">{{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 }}</ref><ref name="pmid14730019">{{cite journal | vauthors = Chan CC, Dostie J, Diem MD, Feng W, Mann M, [[Juri Rappsilber|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 }}</ref> respectively.

==Proteins==
The 407 residue,<ref name="pmid8521730" /> 46 kDa,<ref name="pmid10590115">{{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 }}</ref> 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 [[Splicing (genetics)|RNA splicing]] as well as translation initiation.<ref name="pmid1378397">{{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}}</ref> Crystallographic analysis of yeast eIF4A carried out by Carruthers ''et al.'' (2000)<ref name="pmid11087862">{{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 }}</ref> 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.<ref name="pmid18316401">{{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 }}</ref>

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.<ref name="pmid8449919">{{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 }}</ref> 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.<ref name="pmid16030146">{{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 }}</ref>

== See also ==
* [[Eukaryotic initiation factor]]
* [[Eukaryotic initiation factor 4F|Eukaryotic initiation factor 4F (eIF4F)]]
* [[Hippuristanol]]
* [[Rocaglamide]]

== References ==
{{Reflist|2}}

[[Category:Human proteins]]

EIF4A - Revision history

imported>InternetArchiveBot: Rescuing 0 sources and tagging 1 as dead.) #IABot (v2.0.9.5) (Maxim Masiutin - 17931