EIF4B

{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''Eukaryotic translation initiation factor 4B''' is a protein that in humans is encoded by the ''EIF4B'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: EIF4B eukaryotic translation initiation factor 4B | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1975 }}</ref>

== Structure ==

EIF4B is characterized by a single folded RNA recognition motif (RRM) near its N-terminus, which adopts a classical beta alpha beta beta alpha beta topology. This RRM is responsible for RNA binding but interacts with RNA relatively weakly on its own; high-affinity binding is facilitated by adjacent N- and C-terminal extensions. The majority of the EIF4B protein, encompassing roughly 400 amino acids downstream of the RRM, is intrinsically disordered and forms what is known as the intrinsically disordered region (IDR). This IDR does not adopt a stable three-dimensional structure but instead enables dynamic interactions, self-association, and the formation of large oligomers and biomolecular condensates under certain cellular conditions. A short helical segment within the IDR, coinciding with an arginine-rich motif (ARM), further contributes to RNA binding.<ref name = "Fleming_2003">{{cite journal | vauthors = Fleming K, Ghuman J, Yuan X, Simpson P, Szendröi A, Matthews S, Curry S | title = Solution structure and RNA interactions of the RNA recognition motif from eukaryotic translation initiation factor 4B | journal = Biochemistry | volume = 42 | issue = 30 | pages = 8966–8975 | date = Aug 2003 | pmid = 12885229 | doi = 10.1021/bi034506g }}</ref><ref name = "Swain_2024" />

Mammalian eIF4B acts as a dimer, and other studies had shown that it could form higher-order oligomers as well, through intrinsically disordered regions (IDR).<ref name = "Swain_2024">{{Cite journal | vauthors = Swain BC, Sarkis P, Ung V, Rousseau S, Fernandez L, Meltonyan A, Aho VE, Mercadante D, Mackereth CD, Aznauryan M | title = Disordered regions of human eIF4B orchestrate a dynamic self-association landscape | journal = Nature Communications | volume = 15 | issue = 1 | article-number = 8766 | date = 2024-10-10 | pmid = 39384813 | doi = 10.1038/s41467-024-53136-1 | bibcode = 2024NatCo..15.8766S | language = en | issn = 2041-1723 | pmc = 11464913 }}</ref>

== Function ==

Eukaryotic translation initiation factor 4B (EIF4B) is a multidomain protein essential for efficient cap-dependent translation in eukaryotic cells. Structurally, EIF4B contains a single folded RNA recognition motif (RRM) near its N-terminus.<ref name = "Fleming_2003" /><ref name = "IPR033107">{{cite web | url = https://www.ebi.ac.uk/interpro/entry/InterPro/IPR033107/ | title = Eukaryotic translation initiation factor 4B, RNA recognition motif | work = InterPro | id = IPR033107 }}</ref><ref name = "CD12402">{{cite web | url = https://www.ebi.ac.uk/interpro/entry/cdd/CD12402/ | title = RNA recognition motif (RRM) found in eukaryotic translation initiation factor 4B (eIF-4B) and similar proteins | work = InterPro | id = CD12402 }}</ref> This RRM is responsible for RNA binding but interacts with RNA relatively weakly on its own; high-affinity binding is facilitated by adjacent N- and C-terminal extensions.<ref name = "Fleming_2003" /><ref name = "Méthot_1994">{{cite journal | vauthors = Méthot N, Pause A, Hershey JW, Sonenberg N | title = The translation initiation factor eIF-4B contains an RNA-binding region that is distinct and independent from its ribonucleoprotein consensus sequence | journal = Molecular and Cellular Biology | volume = 14 | issue = 4 | pages = 2307–2316 | date = Apr 1994 | pmid = 8139536 | pmc = 358597 | doi = 10.1128/mcb.14.4.2307 }}</ref> The majority of the EIF4B protein, encompassing roughly 400 amino acids downstream of the RRM, is intrinsically disordered and forms what is known as the intrinsically disordered region (IDR).<ref name = "Swain_2024" /> This IDR does not adopt a stable three-dimensional structure but instead enables dynamic interactions, self-association, and the formation of large oligomers and biomolecular condensates under certain cellular conditions.<ref name = "Swain_2024" /> A short helical segment within the IDR, coinciding with an arginine-rich motif (ARM), further contributes to RNA binding.<ref name = "Swain_2024" /> The flexible and highly dynamic nature of the IDR allows EIF4B to orchestrate diverse molecular interactions critical for translation initiation, including stimulation of the helicase activity of eIF4A and supporting the assembly of other components of the translation initiation machinery.<ref name="Harms_2014">{{cite journal | vauthors = Harms U, Andreou AZ, Gubaev A, Klostermeier D | title = eIF4B, eIF4G and RNA regulate eIF4A activity in translation initiation by modulating the eIF4A conformational cycle | journal = Nucleic Acids Research | volume = 42 | issue = 12 | pages = 7911–22 | date = July 2014 | pmid = 24848014 | pmc = 4081068 | doi = 10.1093/nar/gku440 | url = }}</ref>

EIF4B is a critical protein in the process of cap-dependent translation initiation in eukaryotic cells. Its primary function is to enhance the helicase activity of eIF4A, a DEAD-box RNA helicase, by stimulating its ability to unwind secondary structures in the 5′ untranslated regions (UTRs) of mRNAs[9].<ref name="Harms_2014" /><ref name="Cheng_2006">{{cite journal | vauthors = Cheng S, Gallie DR | title = Wheat eukaryotic initiation factor 4B organizes assembly of RNA and eIFiso4G, eIF4A, and poly(A)-binding protein | journal = The Journal of Biological Chemistry | volume = 281 | issue = 34 | pages = 24351–64 | date = August 2006 | pmid = 16803875 | doi = 10.1074/jbc.M605404200 | doi-access = free }}</ref> This unwinding activity is vital for the ribosome to scan along the mRNA and locate the start codon efficiently. eIF4B also acts as a scaffold by interacting with other translation initiation factors, such as eIF3 and eIF4F, facilitating the assembly of the translation initiation complex.<ref>{{cite journal | vauthors = Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N | title = The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity | journal = The EMBO Journal | volume = 25 | issue = 12 | pages = 2781–2791 | date = Jun 2006 | pmid = 16763566 | pmc = 1500846 | doi = 10.1038/sj.emboj.7601166 }}</ref> Furthermore, eIF4B’s RNA binding capacity—mediated both by its RNA recognition motif (RRM) and its arginine-rich motif (ARM)—directly supports the recruitment and stabilization of mRNA on the ribosome, ensuring efficient and accurate initiation of protein synthesis.<ref name = "Fleming_2003" /><ref name = "Méthot_1994" /> The multifaceted functions of eIF4B are essential for regulating translational output and adapting protein synthesis to cellular conditions.<ref name="Shahbazian_2010">{{cite journal | vauthors = Shahbazian D, Parsyan A, Petroulakis E, Hershey J, Sonenberg N | title = eIF4B controls survival and proliferation and is regulated by proto-oncogenic signaling pathways | journal = Cell Cycle | volume = 9 | issue = 20 | pages = 4106–9 | date = October 2010 | pmid = 20948310 | pmc = 3055195 | doi = 10.4161/cc.9.20.13630 }}</ref>

eIF4B has been shown to interact with and stimulate the enzymatic/RNA helicase activity of eIF4A, also increasing its RNA and ATP binding activity, and bind to the eIF3 complex through the eIF3A subunit.<ref name="Merrick_2015">{{cite journal | vauthors = Merrick WC | title = eIF4F: a retrospective | journal = The Journal of Biological Chemistry | volume = 290 | issue = 40 | pages = 24091–24099 | date = Oct 2015 | pmid = 26324716 | pmc = 4591800 | doi = 10.1074/jbc.R115.675280 | doi-access = free }}</ref> This interaction results in the recruitment of the eukaryotic small ribosomal subunit (40S) to the mRNA which will in turn set the stage for the later steps leading to elongation.

== Clinical significance ==

eIF4B is overexpressed in cancer cells and certain studies had named eIF4B as a potential therapeutic target for treatment of certain types of cancer.<ref>{{Cite journal | vauthors = Chen K, Yang J, Li J, Wang X, Chen Y, Huang S, Chen JL | title = eIF4B is a convergent target and critical effector of oncogenic Pim and PI3K/Akt/mTOR signaling pathways in Abl transformants | journal = Oncotarget | volume = 7 | issue = 9 | pages = 10073–10089 | date = 2016-02-03 | pmid = 26848623 | doi = 10.18632/oncotarget.7164 | url = https://www.oncotarget.com/article/7164/text/ | language = en | issn = 1949-2553 | pmc = 4891105 }}</ref>

== See also == *Eukaryotic translation *eIF4F

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = van Heugten HA, Kasperaitis MA, Thomas AA, Voorma HO | title = Evidence that eukaryotic initiation factor (eIF) 2 is a cap-binding protein that stimulates cap recognition by eIF-4B and eIF-4F | journal = Journal of Biological Chemistry | volume = 266 | issue = 11 | pages = 7279–7284 | date = Apr 1991 | pmid = 2016328 | doi = 10.1016/S0021-9258(20)89641-0 | doi-access = free }} * {{cite journal | vauthors = Milburn SC, Hershey JW, Davies MV, Kelleher K, Kaufman RJ | title = Cloning and expression of eukaryotic initiation factor 4B cDNA: sequence determination identifies a common RNA recognition motif | journal = The EMBO Journal | volume = 9 | issue = 9 | pages = 2783–2790 | date = Sep 1990 | pmid = 2390971 | pmc = 551988 | doi = 10.1002/j.1460-2075.1990.tb07466.x }} * {{cite journal | vauthors = Howe JG, Hershey JW | title = Translational initiation factor and ribosome association with the cytoskeletal framework fraction from HeLa cells | journal = Cell | volume = 37 | issue = 1 | pages = 85–93 | date = May 1984 | pmid = 6722878 | doi = 10.1016/0092-8674(84)90303-9 | doi-access = free }} * {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–174 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }} * {{cite journal | vauthors = Naranda T, Strong WB, Menaya J, Fabbri BJ, Hershey JW | title = Two structural domains of initiation factor eIF-4B are involved in binding to RNA | journal = Journal of Biological Chemistry | volume = 269 | issue = 20 | pages = 14465–14472 | date = May 1994 | pmid = 8182051 | doi = 10.1016/S0021-9258(17)36646-2 | doi-access = free }} * {{cite journal | vauthors = Méthot N, Song MS, Sonenberg N | title = A region rich in aspartic acid, arginine, tyrosine, and glycine (DRYG) mediates eukaryotic initiation factor 4B (eIF4B) self-association and interaction with eIF3 | journal = Molecular and Cellular Biology | volume = 16 | issue = 10 | pages = 5328–5334 | date = Oct 1996 | pmid = 8816444 | pmc = 231531 | doi = 10.1128/MCB.16.10.5328 }} * {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–156 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }} * {{cite journal | vauthors = Richter NJ, Rogers GW, Hensold JO, Merrick WC | title = Further biochemical and kinetic characterization of human eukaryotic initiation factor 4H | journal = Journal of Biological Chemistry | volume = 274 | issue = 50 | pages = 35415–35424 | date = Dec 1999 | pmid = 10585411 | doi = 10.1074/jbc.274.50.35415 | doi-access = free }} * {{cite journal | vauthors = Bushell M, Wood W, Clemens MJ, Morley SJ | title = Changes in integrity and association of eukaryotic protein synthesis initiation factors during apoptosis | journal = European Journal of Biochemistry | volume = 267 | issue = 4 | pages = 1083–1091 | date = Feb 2000 | pmid = 10672017 | doi = 10.1046/j.1432-1327.2000.01101.x | doi-access = free }} * {{cite journal | vauthors = Bushell M, Wood W, Carpenter G, Pain VM, Morley SJ, Clemens MJ | title = Disruption of the interaction of mammalian protein synthesis eukaryotic initiation factor 4B with the poly(A)-binding protein by caspase- and viral protease-mediated cleavages | journal = Journal of Biological Chemistry | volume = 276 | issue = 26 | pages = 23922–23928 | date = Jun 2001 | pmid = 11274152 | doi = 10.1074/jbc.M100384200 | doi-access = free }} * {{cite journal | vauthors = Fleming K, Ghuman J, Yuan X, Simpson P, Szendröi A, Matthews S, Curry S | title = Solution structure and RNA interactions of the RNA recognition motif from eukaryotic translation initiation factor 4B | journal = Biochemistry | volume = 42 | issue = 30 | pages = 8966–8975 | date = Aug 2003 | pmid = 12885229 | doi = 10.1021/bi034506g }} * {{cite journal | vauthors = Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW | title = Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases | journal = The EMBO Journal | volume = 23 | issue = 8 | pages = 1761–1769 | date = Apr 2004 | pmid = 15071500 | pmc = 394247 | doi = 10.1038/sj.emboj.7600193 }} * {{cite journal | vauthors = Doepker RC, Hsu WL, Saffran HA, Smiley JR | title = Herpes simplex virus virion host shutoff protein is stimulated by translation initiation factors eIF4B and eIF4H | journal = Journal of Virology | volume = 78 | issue = 9 | pages = 4684–4699 | date = May 2004 | pmid = 15078951 | pmc = 387725 | doi = 10.1128/JVI.78.9.4684-4699.2004 }} * {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12130–12135 | date = Aug 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 | bibcode = 2004PNAS..10112130B | doi-access = free }} * {{cite journal | vauthors = Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S | title = Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions | journal = Genome Research | volume = 14 | issue = 9 | pages = 1711–1718 | date = Sep 2004 | pmid = 15342556 | pmc = 515316 | doi = 10.1101/gr.2435604 }} * {{cite journal | vauthors = Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M | title = Global, in vivo, and site-specific phosphorylation dynamics in signaling networks | journal = Cell | volume = 127 | issue = 3 | pages = 635–648 | date = Nov 2006 | pmid = 17081983 | doi = 10.1016/j.cell.2006.09.026 | s2cid = 7827573 | doi-access = free }} {{refend}}