| Eukaryotic translation initiation factor 4E |
PDB rendering based on 1ej1. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1IPB, 1IPC, 1WKW, 2GPQ, 2V8W, 2V8X, 2V8Y, 2W97, 3AM7, 3TF2, 3U7X, 4AZA, 4DT6, 4DUM
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| Identifiers |
| Symbols |
EIF4E (; AUTS19; CBP; EIF4E1; EIF4EL1; EIF4F) |
| External IDs |
OMIM: 133440 MGI: 95305 HomoloGene: 123817 ChEMBL: 4848 GeneCards: EIF4E Gene |
| Gene Ontology |
| Molecular function |
• RNA cap binding
• translation initiation factor activity
• protein binding
• eukaryotic initiation factor 4G binding
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| Cellular component |
• cytoplasmic mRNA processing body
• cytosol
• mRNA cap binding complex
• cytoplasmic stress granule
• eukaryotic translation initiation factor 4F complex
• RNA-induced silencing complex
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| Biological process |
• G1/S transition of mitotic cell cycle
• nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay
• nuclear-transcribed mRNA poly(A) tail shortening
• mRNA export from nucleus
• translation
• translational initiation
• regulation of translation
• insulin receptor signaling pathway
• gene expression
• RNA metabolic process
• mRNA metabolic process
• virus-host interaction
• cytokine-mediated signaling pathway
• lung development
• cellular protein metabolic process
• positive regulation of mitotic cell cycle
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
1977 |
13684 |
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| Ensembl |
ENSG00000151247 |
ENSMUSG00000028156 |
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| UniProt |
P06730 |
P63073 |
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| RefSeq (mRNA) |
NM_001130678 |
NM_007917 |
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| RefSeq (protein) |
NP_001124150 |
NP_031943 |
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| Location (UCSC) |
Chr 4:
99.79 – 99.85 Mb |
Chr 3:
138.53 – 138.56 Mb |
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| PubMed search |
[1] |
[2] |
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Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.[1][2]
Contents
- 1 Function
- 1.1 FMRP represses translation through EIF4E binding
- 2 Interactions
- 3 See also
- 4 References
- 5 External links
- 6 Further reading
Function[edit]
All eukaryotic cellular mRNAs are blocked at their 5-prime ends with the 7-methyl-guanosine cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. EIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs. It is a 24-kD polypeptide that exists as both a free form and as part of a multiprotein complex termed EIF4F. The EIF4E polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis. The other subunits of EIF4F are a 50-kD polypeptide, termed EIF4A, that possesses ATPase and RNA helicase activities, and a 220-kD polypeptide, EIF4G.[3][4]
eIF4E's function is to bind an mRNA cap and ultimately bring it to the ribosome. eIF4E is part of the eIF4F pre-initiation complex, which is made up of eIF4E, and eIF4G (eIF4F is sometimes considered to have additional protein components). Almost all cellular proteins require eIF4E in order to be translated into protein. eIF4E binds the first nucleotide on the 5' end of an mRNA molecule (known as the cap): a 7 methyl guanosine (m7G). It sandwiches m7G between 2 tryptophan residues, and other amino acids are involved in the binding.
Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an IRES structure in the RNA.
FMRP represses translation through EIF4E binding[edit]
Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1.[5] RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.[6] In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.[5]
Interactions[edit]
EIF4E has been shown to interact with EIF4A1,[7][8] EIF4EBP3,[9][10] EIF4EBP1,[7][8][11][12][13][14][15][16][17][18][19][20][21] EIF4EBP2,[12][22] Eukaryotic translation initiation factor 4 gamma,[8][12][17][23][24] EIF4G2[25] and EIF4ENIF1.[26]
See also[edit]
- Eukaryotic initiation factors
References[edit]
- ^ Pelletier J, Brook JD, Housman DE (August 1991). "Assignment of two of the translation initiation factor-4E (EIF4EL1 and EIF4EL2) genes to human chromosomes 4 and 20". Genomics 10 (4): 1079–82. doi:10.1016/0888-7543(91)90203-Q. PMID 1916814.
- ^ Jones RM, MacDonald ME, Branda J, Altherr MR, Louis DN, Schmidt EV (May 1997). "Assignment of the human gene encoding eukaryotic initiation factor 4E (EIF4E) to the region q21-25 on chromosome 4". Somat. Cell Mol. Genet. 23 (3): 221–3. doi:10.1007/BF02721373. PMID 9330633.
- ^ Rychlik W, Domier LL, Gardner PR, Hellmann GM, Rhoads RE (February 1987). "Amino acid sequence of the mRNA cap-binding protein from human tissues". Proc. Natl. Acad. Sci. U.S.A. 84 (4): 945–9. doi:10.1073/pnas.84.4.945. PMC 304336. PMID 3469651.
- ^ "Entrez Gene: eIF4E Eukaryotic translation initiation factor 4E".
- ^ a b Napoli, I.; Mercaldo, V.; Boyl, P. P.; Eleuteri, B.; Zalfa, F.; De Rubeis, S.; Di Marino, D.; Mohr, E.; Massimi, M.; Falconi, M.; Witke, W.; Costa-Mattioli, M.; Sonenberg, N.; Achsel, T.; Bagni, C. (2008). "The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP". Cell 134 (6): 1042–1054. doi:10.1016/j.cell.2008.07.031. PMID 18805096. edit
- ^ Zalfa, F.; Giorgi, M.; Primerano, B.; Moro, A.; Di Penta, A.; Reis, S.; Oostra, B.; Bagni, C. (2003). "The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses". Cell 112 (3): 317–327. doi:10.1016/S0092-8674(03)00079-5. PMID 12581522. edit
- ^ a b Ewing, Rob M; Chu Peter, Elisma Fred, Li Hongyan, Taylor Paul, Climie Shane, McBroom-Cerajewski Linda, Robinson Mark D, O'Connor Liam, Li Michael, Taylor Rod, Dharsee Moyez, Ho Yuen, Heilbut Adrian, Moore Lynda, Zhang Shudong, Ornatsky Olga, Bukhman Yury V, Ethier Martin, Sheng Yinglun, Vasilescu Julian, Abu-Farha Mohamed, Lambert Jean-Philippe, Duewel Henry S, Stewart Ian I, Kuehl Bonnie, Hogue Kelly, Colwill Karen, Gladwish Katharine, Muskat Brenda, Kinach Robert, Adams Sally-Lin, Moran Michael F, Morin Gregg B, Topaloglou Thodoros, Figeys Daniel (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. (England) 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
- ^ a b c Connolly, Eileen; Braunstein Steve, Formenti Silvia, Schneider Robert J (May 2006). "Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells". Mol. Cell. Biol. (United States) 26 (10): 3955–65. doi:10.1128/MCB.26.10.3955-3965.2006. ISSN 0270-7306. PMC 1489005. PMID 16648488.
- ^ Kleijn, Miranda; Scheper Gert C, Wilson Mary L, Tee Andrew R, Proud Christopher G (December 2002). "Localisation and regulation of the eIF4E-binding protein 4E-BP3". FEBS Lett. (Netherlands) 532 (3): 319–23. doi:10.1016/S0014-5793(02)03694-3. ISSN 0014-5793. PMID 12482586.
- ^ Poulin, F; Gingras A C, Olsen H, Chevalier S, Sonenberg N (May 1998). "4E-BP3, a new member of the eukaryotic initiation factor 4E-binding protein family". J. Biol. Chem. (UNITED STATES) 273 (22): 14002–7. doi:10.1074/jbc.273.22.14002. ISSN 0021-9258. PMID 9593750.
- ^ Rual, Jean-François; Venkatesan Kavitha, Hao Tong, Hirozane-Kishikawa Tomoko, Dricot Amélie, Li Ning, Berriz Gabriel F, Gibbons Francis D, Dreze Matija, Ayivi-Guedehoussou Nono, Klitgord Niels, Simon Christophe, Boxem Mike, Milstein Stuart, Rosenberg Jennifer, Goldberg Debra S, Zhang Lan V, Wong Sharyl L, Franklin Giovanni, Li Siming, Albala Joanna S, Lim Janghoo, Fraughton Carlene, Llamosas Estelle, Cevik Sebiha, Bex Camille, Lamesch Philippe, Sikorski Robert S, Vandenhaute Jean, Zoghbi Huda Y, Smolyar Alex, Bosak Stephanie, Sequerra Reynaldo, Doucette-Stamm Lynn, Cusick Michael E, Hill David E, Roth Frederick P, Vidal Marc (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature (England) 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
- ^ a b c Mader, S; Lee H, Pause A, Sonenberg N (September 1995). "The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins". Mol. Cell. Biol. (UNITED STATES) 15 (9): 4990–7. ISSN 0270-7306. PMC 230746. PMID 7651417.
- ^ Rao, Ravi D; Mladek Ann C, Lamont Jeffrey D, Goble Jennie M, Erlichman Charles, James C David, Sarkaria Jann N (October 2005). "Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells". Neoplasia (United States) 7 (10): 921–9. doi:10.1593/neo.05361. ISSN 1522-8002. PMC 1502028. PMID 16242075.
- ^ Eguchi, Satoshi; Tokunaga Chiharu, Hidayat Sujuti, Oshiro Noriko, Yoshino Ken-ichi, Kikkawa Ushio, Yonezawa Kazuyoshi (July 2006). "Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size". Genes Cells (England) 11 (7): 757–66. doi:10.1111/j.1365-2443.2006.00977.x. ISSN 1356-9597. PMID 16824195.
- ^ Yang, D; Brunn G J, Lawrence J C (June 1999). "Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR". FEBS Lett. (NETHERLANDS) 453 (3): 387–90. doi:10.1016/S0014-5793(99)00762-0. ISSN 0014-5793. PMID 10405182.
- ^ Patel, Jashmin; McLeod Laura E, Vries Robert G J, Flynn Andrea, Wang Xuemin, Proud Christopher G (June 2002). "Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors". Eur. J. Biochem. (Germany) 269 (12): 3076–85. doi:10.1046/j.1432-1033.2002.02992.x. ISSN 0014-2956. PMID 12071973.
- ^ a b Kumar, V; Sabatini D, Pandey P, Gingras A C, Majumder P K, Kumar M, Yuan Z M, Carmichael G, Weichselbaum R, Sonenberg N, Kufe D, Kharbanda S (April 2000). "Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase". J. Biol. Chem. (UNITED STATES) 275 (15): 10779–87. doi:10.1074/jbc.275.15.10779. ISSN 0021-9258. PMID 10753870.
- ^ Kumar, V; Pandey P, Sabatini D, Kumar M, Majumder P K, Bharti A, Carmichael G, Kufe D, Kharbanda S (March 2000). "Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation". EMBO J. (ENGLAND) 19 (5): 1087–97. doi:10.1093/emboj/19.5.1087. ISSN 0261-4189. PMC 305647. PMID 10698949.
- ^ Gingras, A C; Gygi S P, Raught B, Polakiewicz R D, Abraham R T, Hoekstra M F, Aebersold R, Sonenberg N (June 1999). "Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism". Genes Dev. (UNITED STATES) 13 (11): 1422–37. doi:10.1101/gad.13.11.1422. ISSN 0890-9369. PMC 316780. PMID 10364159.
- ^ Shen, X; Tomoo K, Uchiyama S, Kobayashi Y, Ishida T (October 2001). "Structural and thermodynamic behavior of eukaryotic initiation factor 4E in supramolecular formation with 4E-binding protein 1 and mRNA cap analogue, studied by spectroscopic methods". Chem. Pharm. Bull. (Japan) 49 (10): 1299–303. doi:10.1248/cpb.49.1299. ISSN 0009-2363. PMID 11605658.
- ^ Adegoke, Olasunkanmi A J; Chevalier Stéphanie, Morais José A, Gougeon Réjeanne, Kimball Scot R, Jefferson Leonard S, Wing Simon S, Marliss Errol B (January 2009). "Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men". Am. J. Physiol. Endocrinol. Metab. (United States) 296 (1): E105–13. doi:10.1152/ajpendo.90752.2008. ISSN 0193-1849. PMC 2636991. PMID 18957614.
- ^ Pause, A; Belsham G J, Gingras A C, Donzé O, Lin T A, Lawrence J C, Sonenberg N (October 1994). "Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function". Nature (ENGLAND) 371 (6500): 762–7. doi:10.1038/371762a0. ISSN 0028-0836. PMID 7935831.
- ^ Vary, T C; Jefferson L S, Kimball S R (December 1999). "Amino acid-induced stimulation of translation initiation in rat skeletal muscle". Am. J. Physiol. (UNITED STATES) 277 (6 Pt 1): E1077–86. ISSN 0002-9513. PMID 10600798.
- ^ Harris, Thurl E; Chi An, Shabanowitz Jeffrey, Hunt Donald F, Rhoads Robert E, Lawrence John C (April 2006). "mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin". EMBO J. (England) 25 (8): 1659–68. doi:10.1038/sj.emboj.7601047. ISSN 0261-4189. PMC 1440840. PMID 16541103.
- ^ Gradi, A; Imataka H, Svitkin Y V, Rom E, Raught B, Morino S, Sonenberg N (January 1998). "A novel functional human eukaryotic translation initiation factor 4G". Mol. Cell. Biol. (UNITED STATES) 18 (1): 334–42. ISSN 0270-7306. PMC 121501. PMID 9418880.
- ^ Dostie, J; Ferraiuolo M, Pause A, Adam S A, Sonenberg N (June 2000). "A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5' cap-binding protein, eIF4E". EMBO J. (ENGLAND) 19 (12): 3142–56. doi:10.1093/emboj/19.12.3142. ISSN 0261-4189. PMC 203362. PMID 10856257.
External links[edit]
- Cap-dependent translation initiation from Nature Reviews Microbiology. A good image and overview of the function of initiation factors.
Further reading[edit]
- Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects". Current Problems in Cancer 28 (5): 265–86. doi:10.1016/j.currproblcancer.2004.05.003. PMID 15375804.
- Culjkovic B, Topisirovic I, Borden KL (2007). "Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E". Cell Cycle 6 (1): 65–9. doi:10.4161/cc.6.1.3688. PMID 17245113.
- Malys N, McCarthy JEG (2010). "Translation initiation: variations in the mechanism can be anticipated". Cellular and Molecular Life Sciences 68 (6): 991–1003. doi:10.1007/s00018-010-0588-z. PMID 21076851.
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PDB gallery
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1ej1: COCRYSTAL STRUCTURE OF THE MESSENGER RNA 5' CAP-BINDING PROTEIN (EIF4E) BOUND TO 7-METHYL-GDP
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1ej4: COCRYSTAL STRUCTURE OF EIF4E/4E-BP1 PEPTIDE
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1ejh: EIF4E/EIF4G PEPTIDE/7-METHYL-GDP
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1ipb: CRYSTAL STRUCTURE OF EUKARYOTIC INITIATION FACTOR 4E COMPLEXED WITH 7-METHYL GPPPA
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1ipc: CRYSTAL STRUCTURE OF EUKARYOTIC INITIATION FACTOR 4E COMPLEXED WITH 7-METHYL GTP
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1l8b: Cocrystal Structure of the Messenger RNA 5' Cap-binding Protein (eIF4E) bound to 7-methylGpppG
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1wkw: Crystal structure of the ternary complex of eIF4E-m7GpppA-4EBP1 peptide
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2gpq: Cap-free structure of eIF4E suggests basis for its allosteric regulation
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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Protein biosynthesis: translation (prokaryotic, eukaryotic)
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| Ribosomal proteins |
| Initiation factor |
| Prokaryotic |
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| Archaeal |
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| Eukaryotic |
| eIF1 |
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| eIF2 |
- EIF2S1
- EIF2S2
- EIF2S3
- EIF2B1
- EIF2B2
- EIF2B3
- EIF2B4
- EIF2B5
- EIF-2 kinase
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| eIF3 |
- EIF3A
- B
- C
- D
- F
- G
- H
- I
- J
- K
- M
- S6
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| eIF4 |
- EIF4A2
- A3
- B
- E1
- E2
- G1
- G2
- G3
- H
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| eIF5 |
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| eIF6 |
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| Elongation factor |
| Prokaryotic |
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| Archaeal |
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| Eukaryotic |
- EEF-1
- EEF1A1
- EEF1A2
- EEF1A3
- EEF1B1
- EEF1B2
- EEF1B3
- EEF1B4
- EEF1D
- EEF1E1
- EEF1G
- EEF2
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| Release factor |
- Prokaryotic
- Archaeal
- Eukaryotic (ETF1)
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| Other |
- RPS1
- RPS2
- RPS3
- RPS4
- RPS5
- RPS6
- RPS7
- RPS8
- RPS9
- RPS10
- RPS11
- RPS12
- RPS13
- RPS14
- RPS15
- RPS16
- RPS17
- RPS18
- RPS19
- RPS20
- RPS21
- RPS22
- RPS23
- RPS24
- RPS25
- RPS26
- RPS27
- RPS28
- RPS29
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| Other concepts |
- Aminoacyl tRNA synthetase
- Reading frame
- Start codon
- Stop codon
- Shine-Dalgarno sequence/Kozak consensus sequence
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see also disorders of translation and posttranslational modification
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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