Start codon explained

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.

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. 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. GUG in particular is important to controlling the replication of plasmids.

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.

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).

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.[18]

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.[19] [20] [21]

Engineered start codons

Engineered initiator tRNA (tRNA, changed from a MetY tRNA) 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.[22] (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.[23]

See also

External links

Notes and References

  1. Shetty . S . Shah . RA . Chembazhi . UV . Sah . S . Varshney . U . Two highly conserved features of bacterial initiator tRNAs license them to pass through distinct checkpoints in translation initiation. . Nucleic Acids Research . 28 February 2017 . 45 . 4 . 2040–2050 . 10.1093/nar/gkw854 . 28204695 . 5389676.
  2. Kolitz . SE . Lorsch . JR . Eukaryotic initiator tRNA: finely tuned and ready for action. . FEBS Letters . 21 January 2010 . 584 . 2 . 396–404 . 10.1016/j.febslet.2009.11.047 . 19925799 . 2795131.
  3. 20446809 . 3311535 . 2010 . Lobanov . A. V. . Dual functions of codons in the genetic code . Critical Reviews in Biochemistry and Molecular Biology . 45 . 4 . 257–65 . Turanov . A. A. . Hatfield . D. L. . Gladyshev . V. N. . 10.3109/10409231003786094 .
  4. Asano . K . Why is start codon selection so precise in eukaryotes? . Translation (Austin, Tex.) . 2014 . 2 . 1 . e28387 . 10.4161/trla.28387 . 26779403. 4705826 .
  5. Ivanov . I. P. . Firth . A. E. . Michel . A. M. . Atkins . J. F. . Baranov . P. V. . Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences . 10.1093/nar/gkr007 . Nucleic Acids Research . 39 . 10 . 4220–4234 . 2011 . 21266472 . 3105428 . vanc .
  6. 2538469 . 1989 . Peabody . D. S. . Translation initiation at non-AUG triplets in mammalian cells . The Journal of Biological Chemistry . 264 . 9 . 5031–5. 10.1016/S0021-9258(18)83694-8 . free .
  7. Collado-Vides . C. K. . J. D. . J.. Mayhew. The Complete Genome Sequence of Escherichia coli K-12 . Y.. Shao . B.. Mau . D. J.. Rose . M. A.. Goeden . H. A.. Kirkpatrick . N. W.. Davis . J.. Science. Gregor. 10.1126/science.277.5331.1453 . G. F.. 9278503. 1997. 1453–1462. 277. 5331 . M. . G.. Rode . C. A.. Plunkett g. Perna . F. R.. Riley. Burland. Blattner. Glasner . V. . N. T.. Bloch . free.
  8. Sacerdot . C. . Fayat . G. . Dessen . P. . Springer . M. . Plumbridge . J. A. . Grunberg-Manago . M. . Blanquet . S. . 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 . 1982 . 6325158 . 553041 . 10.1002/j.1460-2075.1982.tb01166.x .
  9. Missiakas . D. . Georgopoulos . C. . Raina . S. . The Escherichia coli heat shock gene htpY: Mutational analysis, cloning, sequencing, and transcriptional regulation . Journal of Bacteriology . 175 . 9 . 2613–2624 . 1993 . 8478327 . 204563 . 10.1128/jb.175.9.2613-2624.1993 .
  10. https://www.ncbi.nlm.nih.gov/nuccore/146575?itemID=6&report=gbwithparts#feature_146575 E.coli lactose operon with lacI, lacZ, lacY and lacA genes GenBank: J01636.1
  11. 10.1038/274765a0 . Farabaugh . P. J. . Sequence of the lacI gene . Nature . 274 . 5673 . 765–769 . 1978 . 355891 . 1978Natur.274..765F . 4208767 .
  12. https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=146575&itemID=4&view=gbwithparts#feature_146575 NCBI Sequence Viewer v2.0
  13. Hecht . Ariel . Glasgow . Jeff . Jaschke . Paul R. . Bawazer . Lukmaan A. . Munson . Matthew S.. Jennifer Cochran . Cochran . Jennifer R. . Endy . Drew . Salit . Marc . Measurements of translation initiation from all 64 codons in E. coli . Nucleic Acids Research . 45 . 7 . 3615–3626 . en . 10.1093/nar/gkx070 . 28334756 . 5397182 . 2017.
  14. Firnberg . Elad . Labonte . Jason . Gray . Jeffrey . Ostermeir . Marc A. . A comprehensive, high-resolution map of a gene's fitness landscape . Molecular Biology and Evolution . 31 . 6 . 1581–1592 . en . 10.1093/molbev/msu081 . 24567513 . 2014 . 4032126.
  15. Book: Watanabe. Kimitsuna. Encyclopedia of Life Sciences. Suzuki. Tsutomu. Genetic Code and its Variants. 2001. 10.1038/npg.els.0000810. 978-0470015902.
  16. Web site: Elzanowski . Andrzej . Ostell . Jim . The Genetic Codes . NCBI . 29 March 2019.
  17. 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 . 10.1186/s13059-022-02674-2 . 1474-760X . 9082881 . 35534899 . free .
  18. RajBhandary . Uttam L. . More surprises in translation: Initiation without the initiator tRNA . Proceedings of the National Academy of Sciences . 15 February 2000 . 97 . 4 . 1325–1327 . 10.1073/pnas.040579197. free . 10677458 . 34295 . 2000PNAS...97.1325R .
  19. Where to Start? Alternate Protein Translation Mechanism Creates Unanticipated Antigens . PLOS Biology . 26 October 2004 . 2 . 11 . e397 . 10.1371/journal.pbio.0020397. free . 524256 .
  20. 22745432 . 2012 . Starck . S. R. . Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I . Science . 336 . 6089 . 1719–23 . Jiang . V . Pavon-Eternod . M . Prasad . S . McCarthy . B . Pan . T . Shastri . N . 10.1126/science.1220270 . 2012Sci...336.1719S. 206540614 .
  21. 22745408 . 2012 . Dever . T. E. . Molecular biology. A new start for protein synthesis . Science . 336 . 6089 . 1645–6 . 10.1126/science.1224439 . 44326947 .
  22. 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 . 10.1073/pnas.87.4.1586 . 2406724 . 53520 . 0027-8424 . 1990PNAS...87.1586V . free .
  23. Vincent . Russel M. . Wright . Bradley W. . Jaschke . Paul R. . 2019-03-15 . Measuring Amber Initiator tRNA Orthogonality in a Genomically Recoded Organism . ACS Synthetic Biology . 8 . 4 . 675–685 . en . 10.1021/acssynbio.9b00021 . 30856316 . 75136654 . 2161-5063 .

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