Nothing Special   »   [go: up one dir, main page]
Jump to content

Eukaryotic initiation factor 3

From Wikipedia, the free encyclopedia
Structure of rabbit eIF3 in the context of the 43S PIC, showing subunits a, c, e, f, h, k, l, and m.[1]

Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation.[2] It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor.[3] The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits (eIF3a, b, c, g, i, j).[4]

Function

[edit]

eIF3 stimulates nearly all steps of translation initiation.[4] eIF3 also appears to participate in other phases of translation, such as recycling, where it promotes the splitting of post-termination ribosomes.[5] In specialized cases of reinitiation following uORFs, eIF3 may remain bound to the ribosome through elongation and termination to promote subsequent initiation events.[6] Research has also indicated that eIF3 plays a role in programmed stop codon readthrough in yeast, by interacting with pre-termination complexes and interfering with decoding.[7]

Interactions

[edit]

eIF3 binds the small ribosomal subunit (40S) at and near its solvent side and serves as a scaffold for several other initiation factors, the auxiliary factor DHX29, and mRNA. eIF3 is a component of the multifactor complex (MFC) and 43S and 48S preinitiation complexes (PICs).[4] The interactions of eIF3 with other initiation factors can vary amongst species; for example, mammalian eIF3 directly interacts with the eIF4F complex (via eIF4G), while budding yeast lacks this connection.[4] However, both mammalian and yeast eIF3 independently bind eIF1, eIF4B, and eIF5.[2][8]

Several subunits of eIF3 contain RNA recognition motifs (RRMs) and other RNA binding domains to form a multisubunit RNA binding interface through which eIF3 interacts with cellular and viral IRES mRNA, including the HCV IRES.[4] eIF3 has also been shown to specifically bind m6A modified RNA within 5'UTRs to promote cap-independent translation.[9]

All five core subunits of budding yeast's eIF3 are present in heat-induced stress granules, along with several other translation factors.[10]

Structure

[edit]

A functional eIF3 complex can be purified from native sources, or reconstituted from recombinantly expressed subunits.[11][12] Individual subunits have been structurally characterized by X-ray crystallography and NMR, while complexes have been characterized by Cryo-EM.[13][14][15] No structure of complete human eIF3 is available, but the nearly-full complex has been determined at medium resolution in the context of the 43S PIC.[1] The structural core of mammalian eIF3 is often described as a five-lobed particle with anthropomorphic features, composed largely of the PCI/MPN octamer.[12] The PCI domains are named for structural similarities between the proteasome cap (P), the COP9 signalosome (C), and eIF3 (I), while the MPN domains are named for structural similarity to the Mpr1-PadI N-terminal domains.[12]

Signaling

[edit]

eIF3 serves as a hub for cellular signaling through S6K1 and mTOR/Raptor.[16] In particular, eIF3 is bound by S6K1 in its inactive state, and activated mTOR/Raptor binds to eIF3 and phosphorylates S6K1 to promote its release from eIF3. Phosphorylated S6K1 is then free to phosphorylate a number of its own targets, including eIF4B, thus serving as a mechanism of translational control.

Disease

[edit]

Individual subunits of eIF3 are overexpressed (a, b, c, h, i, and m) and underexpressed (e, f) in multiple human cancers.[3] In breast cancer and malignant prostate cancer, eIF3h is overexpressed.[17] eIF3 has also been shown to bind a specific set of cell proliferation mRNAs and regulate their translation.[18] eIF3 also functions in the life cycles of a number of important human pathogens, including HIV and HCV. In particular, the d-subunit of eIF3 is a substrate of HIV protease, and genetic knockdown of eIF3 subunits d, e, or f results in increased viral infectivity for unknown reasons.[19]

Subunits

[edit]

The eIF3 subunits exist at equal stoichiometry within the complex, with the exception of eIF3J, which is loosely bound and non-essential for viability in several species.[11][20][21] The subunits were originally organized alphabetically by molecular weight in mammals (A as the highest), but the arrangement of molecular weight can vary between species.[22]

Subunit MW (kDa)[A] Key Features
A 167 Upregulated in several human cancers.[3] Crosslinks directly to cellular mRNA.[18] Contains PCI domain.[12]
B 92 Upregulated in several cancers.[3] Crosslinks directly to cellular mRNA.[18] Contains RRM.[11]
C 105 Upregulated in several cancers.[3] Contains PCI domain.[12] Has a human paralog eIF3CL.
D 64 Dispensable for growth in fission yeast.[4] Crosslinks directly to cellular mRNA[18] and binds the 5'cap of select mRNAs.[23] Substrate of HIV protease.[19]
E 52 Downregulated in breast and lung cancers.[3] Nonessential for growth in fission yeast[24] and Neurospora crassa.[21] Contains PCI domain.[12]
F 38 Downregulated in several cancers.[3] Contains MPN domain.[12]
G 36 Contains RRM.[11] Crosslinks directly to cellular mRNA.[18]
H 40 Upregulated in several cancers.[3] Nonessential for growth in fission yeast,[25] Neurospora crassa,[21] and human cell lines.[26][27] Contains MPN domain.[12]
I 36 Upregulated in several cancers.[3]
J 29 Loosely bound, non-stoichiometric subunit.[4] Binds the 40S ribosomal subunit within the decoding center.[28] Nonessential for growth in budding yeast.[4]
K 25 Nonessential for growth in Neurospora crassa.[21] Contains PCI domain.[12]
L 67 Nonessential for growth in Neurospora crassa.[21] Contains PCI domain.[12]
M 43 Upregulated in human colon cancer.[3]

A Molecular weight of human subunits from Uniprot.

See also

[edit]

References

[edit]
  1. ^ a b des Georges, Amedee; Dhote, Vidya; Kuhn, Lauriane; Hellen, Christopher U.T.; Pestova, Tatyana V.; Frank, Joachim; Hashem, Yaser (2015). "Structure of mammalian eIF3 in the context of the 43S preinitiation complex". Nature. 525 (1770): 491–5. Bibcode:2015Natur.525..491D. doi:10.1038/nature14891. ISSN 0028-0836. PMC 4719162. PMID 26344199.
  2. ^ a b Aitken, Colin E.; Lorsch, Jon R. (2012). "A mechanistic overview of translation initiation in eukaryotes". Nat. Struct. Mol. Biol. 19 (6): 568–576. doi:10.1038/nsmb.2303. PMID 22664984. S2CID 9201095.
  3. ^ a b c d e f g h i j Hershey, John W.B. (2015). "The role of eIF3 and its individual subunits in cancer". Biochim. Biophys. Acta. 1849 (7): 792–800. doi:10.1016/j.bbagrm.2014.10.005. ISSN 1874-9399. PMID 25450521.
  4. ^ a b c d e f g h Hinnebusch, Alan G. (2006). "eIF3: a versatile scaffold for translation initiation complexes". Trends Biochem. Sci. 31 (10): 553–562. doi:10.1016/j.tibs.2006.08.005. ISSN 0968-0004. PMID 16920360.
  5. ^ Pisarev, Andrey V.; Hellen, Christopher U. T.; Pestova, Tatyana V. (2007). "Recycling of eukaryotic post-termination ribosomal complexes". Cell. 131 (2): 286–99. doi:10.1016/j.cell.2007.08.041. PMC 2651563. PMID 17956730.
  6. ^ Sonenberg, Nahum; Hinnebusch, Alan G. (2009). "Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets". Cell. 136 (4): 731–745. doi:10.1016/j.cell.2009.01.042. PMC 3610329. PMID 19239892.
  7. ^ Beznoskova, Petra; Wagner, Susan; Jansen, Myrte Esmeralda; von der Haar, Tobias; Valasek, Leos Shivaya (2015). "Translation initiation factor eIF3 promotes programmed stop codon readthrough". Nucleic Acids Res. 43 (10): 5099–5111. doi:10.1093/nar/gkv421. PMC 4446449. PMID 25925566.
  8. ^ Jackson, Richard J.; Hellen, Christopher U. T.; Pestova, Tatyana V. (2010). "The mechanism of eukaryotic translation initiation and principles of its regulation". Nat. Rev. Mol. Cell Biol. 11 (2): 113–127. doi:10.1038/nrm2838. PMC 4461372. PMID 20094052.
  9. ^ Meyer, Kate D.; Patil, Deepak P.; Zhou, Jun; Zinoviev, Alexandra; Skabkin, Maxim A.; Elemento, Olivier; Pestova, Tatyana V.; Qiang, Shu-Bing; Jaffrey, Samie R. (November 2015). "5' UTR m6A Promotes Cap-Independent Translation". Cell. 163 (4): 999–1010. doi:10.1016/j.cell.2015.10.012. PMC 4695625. PMID 26593424.
  10. ^ Wallace, Edward W.J.; Kear-Scott, Jamie L.; Pilipenko, Evgeny V.; Schwartz, Michael H.; Laskowsk, Pawel R.; Rojek, Alexander E.; Katansk, Christopher D.; Riback, Joshua A.; Dion, Michael F.; Franks, Alexander M.; Airoldi, Edoardo M.; Pan, Tao; Budnik, Bogdan A.; Drummond, D. Allan (2015). "Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress". Cell. 162 (6): 1286–1298. doi:10.1016/j.cell.2015.08.041. PMC 4567705. PMID 26359986.
  11. ^ a b c d Zhou, Min; Sandercock, Alan M.; Fraser, Christopher S.; Ridlova, Gabriela; Stephens, Elaine; Schenauer, Matthew R.; Yokoi-Fong, Theresa; Barsky, Daniel; Leary, Julie A.; Hershey, John W.; Doudna, Jennifer A.; Robinson, Carol V. (Nov 2008). "Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3". Proc. Natl. Acad. Sci. 105 (47): 18139–44. doi:10.1073/pnas.0801313105. PMC 2587604. PMID 18599441.
  12. ^ a b c d e f g h i j Sun, Chaomin; Todorovic, Aleksandar; Querol-Audi, Jordi; Bai, Yun; Villa, Nancy; Snyder, Monica; Ashchyan, John; Lewis, Christopher S.; Hartland, Abbey; Gradia, Scott; Fraser, Christopher S.; Doudna, Jennifer A.; Nogales, Eva; Cate, Jamie H. D. (2011). "Functional reconstitution of human eukaryotic translation initiation factor 3 (eIF3)". Proc. Natl. Acad. Sci. 108 (51): 20473–20478. Bibcode:2011PNAS..10820473S. doi:10.1073/pnas.1116821108. PMC 3251073. PMID 22135459.
  13. ^ Liu, Yi; Neumann, Piotr; Kuhle, Berhard; Monecke, Thomas; Schell, Stephanie; Chari, Ashwin; Ficner, Ralph (2014). "Translation Initiation Factor eIF3b Contains a Nine-Bladed b-Propeller and Interacts with the 40S Ribosomal Subunit". Structure. 22 (6): 923–930. doi:10.1016/j.str.2014.03.010. PMID 24768115.
  14. ^ ElAntak, Latifa; Wagner, Susan; Herrmannova, Anna; Karaskova, Martina; Rutkai, Edit; Lukavsky, Peter J.; Valasek, Leos (2010). "The Indispensable N-Terminal Half of eIF3j/HCR1 Cooperates with its Structurally Conserved Binding Partner eIF3b/PRT1-RRM and with eIF1A in Stringent AUG Selection". J. Mol. Biol. 396 (4): 1097–1116. doi:10.1016/j.jmb.2009.12.047. PMC 2824034. PMID 20060839.
  15. ^ Siridechadilok, Bunpote; Fraser, Christopher S.; Hall, Richard J.; Doudna, Jennifer A.; Nogales, Eva (2005). "Structural Roles for Human Translation Factor eIF3 in Initiation of Protein Synthesis". Science. 310 (5753): 1513–1515. Bibcode:2005Sci...310.1513S. doi:10.1126/science.1118977. PMID 16322461. S2CID 6341705.
  16. ^ Holz, Marina K.; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John (2005). "mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events". Cell. 123 (4): 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006.
  17. ^ Xu, Yichen; Ruggero, Davide (2020). "The Role of Translation Control in Tumorigenesis and Its Therapeutic Implications". Annual Review of Cancer Biology. 4: 437–457. doi:10.1146/annurev-cancerbio-030419-033420.
  18. ^ a b c d e Lee, Amy S.Y.; Kranusch, Philip J.; Cate, Jamie H.D. (2015). "eIF3 targets cell-proliferation messenger RNAs for translational activation or repression". Nature. 522 (7554): 111–114. Bibcode:2015Natur.522..111L. doi:10.1038/nature14267. ISSN 0028-0836. PMC 4603833. PMID 25849773.
  19. ^ a b Jäger, Stefanie; Cimermancic, Peter; Gulbahce, Natali; Johnson, Jeffrey R.; McGovern, Kathryn E.; Clarke, Starlynn C.; Shales, Michael; Mercenne, Gaelle; Pache, Lars; Li, Kathy; Hernandez, Hilda; Jang, Gwendolyn M.; Roth, Shoshannah L.; Akiva, Eyal; Marlett, John; Stephens, Melanie; D’Orso, Ivan; Fernandes, Jason; Fahey, Marie; Mahon, Cathal; O’Donoghue, Anthony J.; Todorovic, Aleksandar; Morris, John H.; Maltby, David A.; Alber, Tom; Cagney, Gerard; Bushman, Frederic D.; Young, John A.; Chanda, Sumit K.; Sundquist, Wesley I.; Kortemme, Tanja; Hernandez, Ryan D.; Craik, Charles S.; Burlingame, Alma; Sali, Andrej; Frankel, Alan D.; Krogan, Nevan J. (2011). "Global landscape of HIV–human protein complexes". Nature. 481 (7381): 365–70. doi:10.1038/nature10719. ISSN 0028-0836. PMC 3310911. PMID 22190034.
  20. ^ Valasek, Leos; Hasek, Jiri; Trachsel, Hans; Imre, Esther Maria; Ruis, Helmut (1999). "The Saccharomyces cerevisiae HCR1 Gene Encoding a Homologue of the p35 Subunit of Human Translation Initiation Factor 3 (eIF3) Is a High Copy Suppressor of a Temperature-sensitive Mutation in the Rpg1p Subunit of Yeast eIF3". J. Biol. Chem. 274 (39): 27567–72. doi:10.1074/jbc.274.39.27567. PMID 10488093.
  21. ^ a b c d e Smith, M. Duane; Yu, Gu; Querol-Audí, Jordi; Vogan, Jacob M.; Nitido, Adam; Cate, Jamie H.D. (November 2013). "Human-Like Eukaryotic Translation Initiation Factor 3 from Neurospora crassa". PLOS ONE. 8 (11): e78715. Bibcode:2013PLoSO...878715S. doi:10.1371/journal.pone.0078715. PMC 3826745. PMID 24250809.
  22. ^ Browning, Karen S.; Gallie, Daniel R.; Hershey, John W.B.; Maitra, Umadas; Merrick, William C.; Norbury, Chris (May 2001). "Unified nomenclature for the subunits of eukaryotic initiation factor 3". Trends Biochem. Sci. 26 (5): 284. doi:10.1016/S0968-0004(01)01825-4. PMID 11426420.
  23. ^ Lee, Amy S. Y.; Kranzusch, Philip J.; Doudna, Jennifer A.; Cate, Jamie H. D. (2016-07-27). "eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation". Nature. 536 (7614). Springer Nature: 96–99. Bibcode:2016Natur.536...96L. doi:10.1038/nature18954. ISSN 0028-0836. PMC 5003174. PMID 27462815.
  24. ^ Akiyoshi, Yuji; Clayton, Jason; Phan, Lon; Yamamoto, Masayuki; Hinnebusch, Alan G.; Watanabe, Yoshinori; Asano, Katsura (2000-12-27). "Fission Yeast Homolog of Murine Int-6 Protein, Encoded by Mouse Mammary Tumor Virus Integration Site, Is Associated with the Conserved Core Subunits of Eukaryotic Translation Initiation Factor 3". Journal of Biological Chemistry. 276 (13). American Society for Biochemistry & Molecular Biology (ASBMB): 10056–10062. doi:10.1074/jbc.m010188200. ISSN 0021-9258. PMID 11134033.
  25. ^ Ray, Anirban; Bandyopadhyay, Amitabha; Matsumoto, Tomohiro; Deng, Haiteng; Maitra, Umadas (2008). "Fission yeast translation initiation factor 3 subunit eIF3h is not essential for global translation initiation, but deletion ofeif3h+affects spore formation". Yeast. 25 (11). Wiley-Blackwell: 809–823. doi:10.1002/yea.1635. ISSN 0749-503X. PMID 19061185. S2CID 25980313.
  26. ^ Smith, M. Duane; Arake-Tacca, Luisa; Nitido, Adam; Montabana, Elizabeth; Park, Annsea; Cate, Jamie H. (2016). "Assembly of eIF3 Mediated by Mutually Dependent Subunit Insertion". Structure. 24 (6). Elsevier BV: 886–896. doi:10.1016/j.str.2016.02.024. ISSN 0969-2126. PMC 4938246. PMID 27210288.
  27. ^ Johnson, Alex G.; Petrov, Alexey N.; Fuchs, Gabriele; Majzoub, Karim; Grosely, Rosslyn; Choi, Junhong; Puglisi, Joseph D. (2017-11-09). "Fluorescently-tagged human eIF3 for single-molecule spectroscopy". Nucleic Acids Research. 46 (2). Oxford University Press (OUP): e8. doi:10.1093/nar/gkx1050. ISSN 0305-1048. PMC 5778468. PMID 29136179.
  28. ^ Fraser, Christopher S.; Berry, Katherine E.; Hershey, John W. B.; Doudna, Jennifer A. (2007). "eIF3j Is Located in the Decoding Center of the Human 40S Ribosomal Subunit". Molecular Cell. 26 (6): 811–819. doi:10.1016/j.molcel.2007.05.019. PMID 17588516.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Eukaryotic_initiation_factor_3&oldid=1228947341"