{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:59:48Z","timestamp":1785427188796,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL151392"],"award-info":[{"award-number":["HL151392"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM128981"],"award-info":[{"award-number":["GM128981"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"award":["HL151392"],"award-info":[{"award-number":["HL151392"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GM128981"],"award-info":[{"award-number":["GM128981"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>This article proposes three possible explanations that relate to the process of eukaryotic translation initiation. These explanations suggest mechanisms as to how concentrations of initiation factors (by mass or by posttranslational modification) can influence start site selection, how regulation of translation by 4E-BP (an inhibitor of m7G cap-dependent translation) can be explained by \u201ceIF4F disassembly\u201d and how the scanning mechanism might involve initiation factor binding at the 5\u2032 end of the mRNA to provide for apparent unidirectional Brownian movement to locate the initiating AUG. These represent testable models, although the experiments would not be simple. It is hoped that the insights provided will assist researchers in defining the precise steps and mechanisms of the complex initiation process. It is noted that the better this process is understood, the easier it will be to understand how this process is regulated under a wide variety of biological situations, such as nutritional deprivation, heat shock, cell growth, or disease. Additionally, as initiation is the rate-limiting step in translation, a better understanding of this process should also suggest new avenues to treat various diseases, especially conditions of unrestricted growth.<\/jats:p>","DOI":"10.3390\/genes17070800","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:34:44Z","timestamp":1783996484000},"page":"800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Review of the Uncertainties of Eukaryotic Translation Initiation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4188-0633","authenticated-orcid":false,"given":"Anton A.","family":"Komar","sequence":"first","affiliation":[{"name":"Center for Gene Regulation in Health and Disease, Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-8128","authenticated-orcid":false,"given":"William C.","family":"Merrick","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.cell.2009.01.042","article-title":"Regulation of translation initiation in eukaryotes: Mechanisms and biological targets","volume":"136","author":"Sonenberg","year":"2009","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1146\/annurev-biochem-060713-035802","article-title":"The scanning mechanism of eukaryotic translation initiation","volume":"83","author":"Hinnebusch","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41580-023-00624-9","article-title":"The molecular basis of translation initiation and its regulation in eukaryotes","volume":"25","author":"Ramakrishnan","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1534\/genetics.115.186221","article-title":"Mechanism and regulation of protein synthesis in Saccharomyces cerevisiae","volume":"203","author":"Dever","year":"2016","journal-title":"Genetics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1093\/nar\/gkw1190","article-title":"Insights into the mechanism of eukaryotic translation gained with ribosome profiling","volume":"45","author":"Andreev","year":"2017","journal-title":"Nucleic Acid. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1101\/gad.11.18.2396","article-title":"GTP hydrolysis controls stringent selection of the AUG start codon during translation initiation in Saccharomyces cerevisiae","volume":"11","author":"Huang","year":"1997","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e392273","DOI":"10.7554\/eLife.39273","article-title":"Translation initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition","volume":"7","author":"Llacer","year":"2018","journal-title":"Elife"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e24419","DOI":"10.4161\/trla.24419","article-title":"Influence of translation factor activities on start site selection in six different mRNAs","volume":"1","author":"Basker","year":"2013","journal-title":"Translation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1083\/jcb.108.2.229","article-title":"The scanning model for translation: An update","volume":"108","author":"Kozak","year":"1989","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41586-022-04858-z","article-title":"eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining","volume":"607","author":"Lapointe","year":"2022","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1038\/s41594-025-01629-y","article-title":"eIF1 and eIF5 dynamically control translation start site fidelity","volume":"32","author":"Grosely","year":"2025","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5910","DOI":"10.1021\/acs.biochem.8b00839","article-title":"Human eIF5 and eIF1A compete for binding to eIF5B","volume":"57","author":"Lin","year":"2018","journal-title":"Biochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18056","DOI":"10.1073\/pnas.1009269107","article-title":"Initiation context modulates autoregulation of eukaryotic translation initiation factor 1 (eIF1)","volume":"107","author":"Ivanonv","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1093\/nar\/gkr1192","article-title":"Stringency of start codon selection modulates autoregulation of translation initiation factor eIF5","volume":"40","author":"Loughan","year":"2012","journal-title":"Nucleic Acid. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5006","DOI":"10.1074\/jbc.273.9.5006","article-title":"Functional characterization of the internal ribosome entry site of eIF4G mRNA","volume":"273","author":"Gan","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5804","DOI":"10.1016\/S0021-9258(20)81965-6","article-title":"New initiation factor activity required for globin mRNA translation","volume":"258","author":"Grifo","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7651","DOI":"10.1016\/S0021-9258(17)39658-8","article-title":"ATP-dependent unwinding of messenger RNA structure by eukaryotic initiation factors","volume":"260","author":"Ray","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"gkaf1351","DOI":"10.1093\/nar\/gkaf1351","article-title":"Eukaryotic translation initiation factor 4F: Functional properties and physiological role","volume":"53","author":"Shuvalova","year":"2025","journal-title":"Nucleic Acid. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/bi00297a001","article-title":"Purification of the messenger RNA cap-binding protein using a new affinity medium","volume":"23","author":"Webb","year":"1984","journal-title":"Biochemistry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3826","DOI":"10.1016\/S0021-9258(18)61430-9","article-title":"The ATP-dependent interaction of eukaryotic initiation factors with mRNA","volume":"262","author":"Abramson","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1101\/gad.282418.116","article-title":"Toward the mechanism of eIF4F-mediated ribosomal attachment to mammalian capped mRNAs","volume":"30","author":"Kumar","year":"2016","journal-title":"Genes Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41392-025-02493-4","article-title":"mTOR signaling networks: Mechanistic insights and translational frontiers in disease therapeutics","volume":"10","author":"Zhang","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"mTOR at the nexus of nutrition, growth, ageing and disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.molcel.2020.09.021","article-title":"Stress-Induced Translation Inhibition through Rapid Displacement of Scanning Initiation Factors","volume":"80","author":"Bresson","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116447","DOI":"10.1016\/j.celrep.2025.116447","article-title":"Heat shock induces silent ribosomes and reorganizes mRNA turnover","volume":"44","author":"Rahaman","year":"2025","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1126\/science.aba4904","article-title":"Structure of a human 48S translational initiation complex","volume":"369","author":"Sokabe","year":"2020","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41594-023-01196-0","article-title":"The structure of a human translation initiation complex reveals two independent roles for the helicase eIF4A","volume":"31","author":"Sokabe","year":"2024","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1093\/nar\/gky054","article-title":"Structure of a human cap-dependent 48S translation pre-initiation complex","volume":"46","author":"Eliseev","year":"2018","journal-title":"Nucleic Acid. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5282","DOI":"10.1093\/nar\/gkac283","article-title":"Conformational rearrangements upon start codon recognition in human 48S translation initiation complex","volume":"50","author":"Yi","year":"2022","journal-title":"Nucleic Acid. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/0092-8674(80)90356-6","article-title":"The role of ATP in binding and migration of 40S ribosomal subunits","volume":"22","author":"Kozak","year":"1980","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1021\/bi972430g","article-title":"The DEAD box protein eIF4A. 1. A minimal kinetic and thermodynamic framework reveals coupled binding of RNA and nucleotide","volume":"37","author":"Lorsch","year":"1998","journal-title":"Biochemistry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1016\/j.jmb.2017.10.008","article-title":"Biochemical differences and similarities between the DEAD-Box helicase orthologs DDX3X and Ded1p","volume":"429","author":"Sharma","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nature17978","article-title":"Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor","volume":"534","author":"Iwasaki","year":"2016","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/15476286.2016.1259782","article-title":"eIF4B stimulates eIF4A ATPase and unwinding activities by direct interaction through its 7-repeats region","volume":"14","author":"Andreou","year":"2017","journal-title":"RNA Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1046\/j.1365-2958.2003.03898.x","article-title":"Dynamics and processivity of 40S ribosome scanning on mRNA in yeast","volume":"51","author":"Berthelot","year":"2004","journal-title":"Mol. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4474","DOI":"10.1016\/j.cell.2022.10.005","article-title":"Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation","volume":"185","author":"Wang","year":"2022","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/j.1460-2075.1994.tb06370.x","article-title":"Dominant negative mutants of mammalian translation initiation factor eIF4A define a critical role for eIF4F in cap-dependent cap-independent initiation of translation","volume":"13","author":"Pause","year":"1994","journal-title":"EMBO J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5566","DOI":"10.1016\/S0021-9258(18)53358-5","article-title":"The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF4A","volume":"268","author":"Pause","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10688","DOI":"10.1021\/bi901379a","article-title":"How does a scanning ribosomal particle move along the 5\u2032-untranslated region of eukaryotic mRNA? Brownian ratchet model","volume":"48","author":"Spirin","year":"2008","journal-title":"Biochemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1093\/nar\/gkr147","article-title":"Unidirectional constant rate motion of the ribosomal scanning particle during eukaryotic translation initiation","volume":"39","author":"Vassilenko","year":"2011","journal-title":"Nucleic Acid. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2850","DOI":"10.1073\/pnas.83.9.2850","article-title":"Influences of mRNA secondary structure on initiation by eukaryotic ribosomes","volume":"83","author":"Kozak","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1093\/nar\/14.14.5827","article-title":"Secondary structure model for mouse beta globin mRNA derived from enzymatic digestion data, comparative sequence and computer analysis","volume":"14","author":"Lockard","year":"1986","journal-title":"Nucleic Acid. Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/800\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:47:51Z","timestamp":1783997271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070800"],"URL":"https:\/\/doi.org\/10.3390\/genes17070800","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}