Start codon

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Start codon (blue circle) of the human mitochondrial DNA MT-ATP6 gene. For each nucleotide triplet (square brackets), the corresponding amino acid is given (one-letter code), either in the +1 reading frame for MT-ATP8 (in red) or in the +3 frame for MT-ATP6 (in blue). In this genomic region, the two genes overlap. Homo sapiens-mtDNA~NC 012920-ATP8+ATP6 Overlap.svg
Start codon (blue circle) of the human mitochondrial DNA MT-ATP6 gene. For each nucleotide triplet (square brackets), the corresponding amino acid is given (one-letter code), either in the +1 reading frame for MT-ATP8 (in red) or in the +3 frame for MT-ATP6 (in blue). In this genomic region, the two genes overlap.

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids.

Contents

The start codon is often preceded by a 5' untranslated region (5' UTR). In prokaryotes this includes the ribosome binding site.

Decoding

In all three domains of life, the start codon is decoded by a special "initiation" transfer RNA different from the tRNAs used for elongation. There are important structural differences between an initiating tRNA and an elongating one, with distinguish features serving to satisfy the constraints of the translation system. In bacteria and organelles, an acceptor stem C1:A72 mismatch guide formylation, which directs recruitment by the 30S ribosome into the P site; so-called "3GC" base pairs allow assembly into the 70S ribosome. [1] In eukaryotes and archaea, the T stem prevents the elongation factors from binding, while eIF2 specifically recognizes the attached methionine and a A1:U72 basepair. [2]

In any case, the natural initiating tRNA only codes for methionine. [3] Knowledge of the key recognizing features has allowed researchers to construct alternative initiating tRNAs that code for different amino acids; see below.

Alternative start codons

Alternative start codons are different from the standard AUG codon and are found in both prokaryotes (bacteria and archaea) and eukaryotes. Alternate start codons are still translated as Met when they are at the start of a protein (even if the codon encodes a different amino acid otherwise). This is because a separate tRNA is used for initiation. [3]

Eukaryotes

Alternate start codons (non-AUG) are very rare in eukaryotic genomes: a wide range of mechanisms work to guarantee the relative fidelity of AUG initiation. [4] However, naturally occurring non-AUG start codons have been reported for some cellular mRNAs. [5] Seven out of the nine possible single-nucleotide substitutions at the AUG start codon of dihydrofolate reductase are functional as translation start sites in mammalian cells. [6]

Bacteria

Bacteria do not generally have the wide range of translation factors monitoring start codon fidelity. GUG and UUG are the main, even "canonical", alternate start codons. [4] GUG in particular is important to controlling the replication of plasmids. [4]

E. coli uses 83% AUG (3542/4284), 14% (612) GUG, 3% (103) UUG [7] and one or two others (e.g., an AUU and possibly a CUG). [8] [9]

Well-known coding regions that do not have AUG initiation codons are those of lacI (GUG) [10] [11] and lacA (UUG) [12] in the E. coli lac operon. Two more recent studies have independently shown that 17 or more non-AUG start codons may initiate translation in E. coli. [13] [14]

Mitochondria

Mitochondrial genomes use alternate start codons more significantly (AUA and AUG in humans). [15] Many such examples, with codons, systematic range, and citations, are given in the NCBI list of translation tables. [16]

Archaea

Archaea, which are prokaryotes with a translation machinery similar to but simpler than that of eukaryotes, allow initiation at UUG and GUG. [4]

Upstream start codons

These are "alternative" start codons in the sense that they are upstream of the regular start codons and thus could be used as alternative start codons. More than half of all human mRNAs have at least one AUG codon upstream (uAUG) of their annotated translation initiation starts (TIS) (58% in the current versions of the human RefSeq sequence). Their potential use as TISs could result in translation of so-called upstream Open Reading Frames (uORFs). uORF translation usually results in the synthesis of short polypeptides, some of which have been shown to be functional, e.g., in ASNSD1, MIEF1, MKKS, and SLC35A4. [17] However, it is believed that most translated uORFs only have a mild inhibitory effect on downstream translation because most uORF starts are leaky (i.e. don't initiate translation or because ribosomes terminating after translation of short ORFs are often capable of reinitiating). [17]

Standard genetic code

Amino-acid biochemical propertiesNonpolarPolarBasicAcidicTermination: stop codon
Standard genetic code (NCBI table 1) [18]
1st
base		2nd base3rd
base
UCAG
UUUU(Phe/F) Phenylalanine UCU(Ser/S) Serine UAU(Tyr/Y) Tyrosine UGU(Cys/C) Cysteine U
UUCUCCUACUGCC
UUA(Leu/L) Leucine UCAUAA Stop (Ochre) [B] UGA Stop (Opal) [B] A
UUG [A] UCGUAG Stop (Amber) [B] UGG(Trp/W) Tryptophan G
CCUUCCU(Pro/P) Proline CAU(His/H) Histidine CGU(Arg/R) Arginine U
CUCCCCCACCGCC
CUACCACAA(Gln/Q) Glutamine CGAA
CUGCCGCAGCGGG
AAUU(Ile/I) Isoleucine ACU(Thr/T) Threonine AAU(Asn/N) Asparagine AGU(Ser/S) Serine U
AUCACCAACAGCC
AUAACAAAA(Lys/K) Lysine AGA(Arg/R) Arginine A
AUG [A] (Met/M) Methionine ACGAAGAGGG
GGUU(Val/V) Valine GCU(Ala/A) Alanine GAU(Asp/D) Aspartic acid GGU(Gly/G) Glycine U
GUCGCCGACGGCC
GUAGCAGAA(Glu/E) Glutamic acid GGAA
GUG [A] GCGGAGGGGG
A Possible start codons in NCBI table 1. AUG is most common. [19] The two other start codons listed by table 1 (GUG and UUG) are rare in eukaryotes. [20] Prokaryotes have less strigent start codon requirements; they are described by NCBI table 11.
B ^ ^ ^ The historical basis for designating the stop codons as amber, ochre and opal is described in an autobiography by Sydney Brenner [21] and in a historical article by Bob Edgar. [22]

Non-methionine start codons

Natural

Translation started by an internal ribosome entry site (IRES), which bypasses a number of regular eukaryotic initiation systems, can have a non-methinone start with GCU or CAA codons. [23]

Mammalian cells can initiate translation with leucine using a specific leucyl-tRNA that decodes the codon CUG. This mechanism is independent of eIF2. No secondary structure similar to that of an IRES is needed. It proceeds by ribosomal scanning, and a Kozak context enhances initiation efficiency. [24] [25] [26]

Engineered start codons

Engineered initiator tRNA (tRNAfMet
CUA, changed from a MetY tRNAfMet
CAU) have been used to initiate translation at the amber stop codon UAG in E. coli. Initiation with this tRNA not only inserts the traditional formylmethionine, but also formylglutamine, as glutamyl-tRNA synthase also recognizes the new tRNA. [27] (Recall from above that the bacterial translation initiation system does not specifically check for methionine, only the formyl modification). [1] One study has shown that the amber initiator tRNA does not initiate translation to any measurable degree from genomically-encoded UAG codons, only plasmid-borne reporters with strong upstream Shine-Dalgarno sites. [28]

See also

References

  1. 1 2 Shetty, S; Shah, RA; Chembazhi, UV; Sah, S; Varshney, U (28 February 2017). "Two highly conserved features of bacterial initiator tRNAs license them to pass through distinct checkpoints in translation initiation". Nucleic Acids Research. 45 (4): 2040–2050. doi:10.1093/nar/gkw854. PMC   5389676 . PMID   28204695.
  2. ↑ Kolitz, SE; Lorsch, JR (21 January 2010). "Eukaryotic initiator tRNA: finely tuned and ready for action". FEBS Letters. 584 (2): 396–404. doi:10.1016/j.febslet.2009.11.047. PMC   2795131 . PMID   19925799.
  3. 1 2 Lobanov, A. V.; Turanov, A. A.; Hatfield, D. L.; Gladyshev, V. N. (2010). "Dual functions of codons in the genetic code". Critical Reviews in Biochemistry and Molecular Biology. 45 (4): 257–65. doi:10.3109/10409231003786094. PMC   3311535 . PMID   20446809.
  4. 1 2 3 4 Asano, K (2014). "Why is start codon selection so precise in eukaryotes?". Translation (Austin, Tex.). 2 (1): e28387. doi:10.4161/trla.28387. PMC   4705826 . PMID   26779403.
  5. ↑ Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV (2011). "Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences". Nucleic Acids Research. 39 (10): 4220–4234. doi:10.1093/nar/gkr007. PMC   3105428 . PMID   21266472.
  6. ↑ Peabody, D. S. (1989). "Translation initiation at non-AUG triplets in mammalian cells". The Journal of Biological Chemistry. 264 (9): 5031–5. doi: 10.1016/S0021-9258(18)83694-8 . PMID   2538469.
  7. ↑ Blattner, F. R.; Plunkett g, G.; Bloch, C. A.; Perna, N. T.; Burland, V.; Riley, M.; Collado-Vides, J.; Glasner, J. D.; Rode, C. K.; Mayhew, G. F.; Gregor, J.; Davis, N. W.; Kirkpatrick, H. A.; Goeden, M. A.; Rose, D. J.; Mau, B.; Shao, Y. (1997). "The Complete Genome Sequence of Escherichia coli K-12". Science. 277 (5331): 1453–1462. doi: 10.1126/science.277.5331.1453 . PMID   9278503.
  8. ↑ Sacerdot, C.; Fayat, G.; Dessen, P.; Springer, M.; Plumbridge, J. A.; Grunberg-Manago, M.; Blanquet, S. (1982). "Sequence of a 1.26-kb DNA fragment containing the structural gene for E.coli initiation factor IF3: Presence of an AUU initiator codon". The EMBO Journal. 1 (3): 311–315. doi:10.1002/j.1460-2075.1982.tb01166.x. PMC   553041 . PMID   6325158.
  9. ↑ Missiakas, D.; Georgopoulos, C.; Raina, S. (1993). "The Escherichia coli heat shock gene htpY: Mutational analysis, cloning, sequencing, and transcriptional regulation". Journal of Bacteriology. 175 (9): 2613–2624. doi:10.1128/jb.175.9.2613-2624.1993. PMC   204563 . PMID   8478327.
  10. ↑ E.coli lactose operon with lacI, lacZ, lacY and lacA genes GenBank: J01636.1
  11. ↑ Farabaugh, P. J. (1978). "Sequence of the lacI gene". Nature. 274 (5673): 765–769. Bibcode:1978Natur.274..765F. doi:10.1038/274765a0. PMID   355891. S2CID   4208767.
  12. ↑ NCBI Sequence Viewer v2.0
  13. ↑ Hecht, Ariel; Glasgow, Jeff; Jaschke, Paul R.; Bawazer, Lukmaan A.; Munson, Matthew S.; Cochran, Jennifer R.; Endy, Drew; Salit, Marc (2017). "Measurements of translation initiation from all 64 codons in E. coli". Nucleic Acids Research. 45 (7): 3615–3626. doi:10.1093/nar/gkx070. PMC   5397182 . PMID   28334756.
  14. ↑ Firnberg, Elad; Labonte, Jason; Gray, Jeffrey; Ostermeir, Marc A. (2014). "A comprehensive, high-resolution map of a gene's fitness landscape". Molecular Biology and Evolution. 31 (6): 1581–1592. doi:10.1093/molbev/msu081. PMC   4032126 . PMID   24567513.
  15. ↑ Watanabe, Kimitsuna; Suzuki, Tsutomu (2001). "Genetic Code and its Variants". Encyclopedia of Life Sciences. doi:10.1038/npg.els.0000810. ISBN   978-0470015902.
  16. ↑ Elzanowski, Andrzej; Ostell, Jim. "The Genetic Codes". NCBI. Retrieved 29 March 2019.
  17. 1 2 Andreev, Dmitry E.; Loughran, Gary; Fedorova, Alla D.; Mikhaylova, Maria S.; Shatsky, Ivan N.; Baranov, Pavel V. (2022-05-09). "Non-AUG translation initiation in mammals". Genome Biology. 23 (1): 111. doi: 10.1186/s13059-022-02674-2 . ISSN   1474-760X. PMC   9082881 . PMID   35534899.
  18. ↑ Elzanowski A, Ostell J (7 January 2019). "The Genetic Codes". National Center for Biotechnology Information. Archived from the original on 5 October 2020. Retrieved 21 February 2019.
  19. ↑ Nakamoto T (March 2009). "Evolution and the universality of the mechanism of initiation of protein synthesis". Gene. 432 (1–2): 1–6. doi:10.1016/j.gene.2008.11.001. PMID   19056476.
  20. ↑ Asano, K (2014). "Why is start codon selection so precise in eukaryotes?". Translation (Austin, Tex.). 2 (1): e28387. doi:10.4161/trla.28387. PMID   26779403.
  21. ↑ Brenner S. A Life in Science (2001) Published by Biomed Central Limited ISBN   0-9540278-0-9 see pages 101-104
  22. ↑ Edgar B (2004). "The genome of bacteriophage T4: an archeological dig". Genetics. 168 (2): 575–82. PMC   1448817 . PMID   15514035. see pages 580-581
  23. ↑ RajBhandary, Uttam L. (15 February 2000). "More surprises in translation: Initiation without the initiator tRNA". Proceedings of the National Academy of Sciences. 97 (4): 1325–1327. Bibcode:2000PNAS...97.1325R. doi: 10.1073/pnas.040579197 . PMC   34295 . PMID   10677458.
  24. ↑ "Where to Start? Alternate Protein Translation Mechanism Creates Unanticipated Antigens". PLOS Biology. 2 (11): e397. 26 October 2004. doi: 10.1371/journal.pbio.0020397 . PMC   524256 .
  25. ↑ Starck, S. R.; Jiang, V; Pavon-Eternod, M; Prasad, S; McCarthy, B; Pan, T; Shastri, N (2012). "Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I". Science. 336 (6089): 1719–23. Bibcode:2012Sci...336.1719S. doi:10.1126/science.1220270. PMID   22745432. S2CID   206540614.
  26. ↑ Dever, T. E. (2012). "Molecular biology. A new start for protein synthesis". Science. 336 (6089): 1645–6. doi:10.1126/science.1224439. PMID   22745408. S2CID   44326947.
  27. ↑ Varshney, U.; RajBhandary, U. L. (1990-02-01). "Initiation of protein synthesis from a termination codon". Proceedings of the National Academy of Sciences. 87 (4): 1586–1590. Bibcode:1990PNAS...87.1586V. doi: 10.1073/pnas.87.4.1586 . ISSN   0027-8424. PMC   53520 . PMID   2406724.
  28. ↑ Vincent, Russel M.; Wright, Bradley W.; Jaschke, Paul R. (2019-03-15). "Measuring Amber Initiator tRNA Orthogonality in a Genomically Recoded Organism" (PDF). ACS Synthetic Biology. 8 (4): 675–685. doi:10.1021/acssynbio.9b00021. ISSN   2161-5063. PMID   30856316. S2CID   75136654.
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