Start codon

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.

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

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 transfer RNA (tRNA) is used for initiation.[1]

Eukaryotes

Alternate start codons (non-AUG) are very rare in eukaryotic genomes. However, naturally occurring non-AUG start codons have been reported for some cellular mRNAs.[2] 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.[3] In addition to the canonical Met-tRNA Met and AUG codon pathway, mammalian cells can initiate translation with leucine using a specific leucyl-tRNA that decodes the codon CUG.[4][5]

Candida albicans uses a CAG start codon.[6]

Prokaryotes

Prokaryotes use alternate start codons significantly, mainly GUG and UUG.

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]

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 properties Nonpolar Polar Basic Acidic Termination: stop codon
Standard genetic code
1st
base		 2nd base 3rd
base
U C A G
U UUU (Phe/F) Phenylalanine UCU (Ser/S) Serine UAU (Tyr/Y) Tyrosine UGU (Cys/C) Cysteine U
UUC UCC UAC UGC C
UUA (Leu/L) Leucine UCA UAA Stop (Ochre)[B] UGA Stop (Opal)[B] A
UUG[A] UCG UAG Stop (Amber)[B] UGG (Trp/W) Tryptophan G
C CUU CCU (Pro/P) Proline CAU (His/H) Histidine CGU (Arg/R) Arginine U
CUC CCC CAC CGC C
CUA CCA CAA (Gln/Q) Glutamine CGA A
CUG[A] CCG CAG CGG G
A AUU (Ile/I) Isoleucine ACU (Thr/T) Threonine AAU (Asn/N) Asparagine AGU (Ser/S) Serine U
AUC ACC AAC AGC C
AUA ACA AAA (Lys/K) Lysine AGA (Arg/R) Arginine A
AUG[A] (Met/M) Methionine ACG AAG AGG G
G GUU (Val/V) Valine GCU (Ala/A) Alanine GAU (Asp/D) Aspartic acid GGU (Gly/G) Glycine U
GUC GCC GAC GGC C
GUA GCA GAA (Glu/E) Glutamic acid GGA A
GUG GCG GAG GGG G
A The codon AUG both codes for methionine and serves as an initiation site: the first AUG in an mRNA's coding region is where translation into protein begins.[18] The other start codons listed by GenBank are rare in eukaryotes and generally codes for Met/fMet.[19]
B ^ ^ ^ The historical basis for designating the stop codons as amber, ochre and opal is described in an autobiography by Sydney Brenner[20] and in a historical article by Bob Edgar.[21]

Engineered start codons

Engineered initiator tRNAs (tRNAfMet2 with CUA anticodon) have been used to initiate translation at the amber stop codon UAG.[22] This type of engineered tRNA is called a nonsense suppressor tRNA because it suppresses the translation stop signal that normally occurs at UAG codons. 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

References
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  4. 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.
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  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.
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  • The Genetic Codes. Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell, National Center for Biotechnology Information (NCBI), Bethesda, Maryland, US
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