Kozak consensus sequence
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The Kozak consensus sequence, Kozak consensus or Kozak sequence, is a sequence which occurs on eukaryotic mRNA and has the consensus (gcc)gccRccAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another 'G'.[1] The Kozak consensus sequence plays a major role in the initiation of translation process.[2]
This sequence on an mRNA molecule is recognized by the ribosome as the translational start site, from which point a protein is coded by that mRNA molecule. The ribosome requires this sequence, or a possible variation (see below) to initiate translation. The Kozak sequence is not to be confused with the ribosomal binding site (RBS), that being either the 5' cap of a messenger RNA or an Internal Ribosome Entry Site (IRES).
In vivo, this site is often not matched exactly on different mRNAs and the amount of protein synthesized from a given mRNA is dependent on the strength of the Kozak sequence.[3] Some nucleotides in this sequence are more important than others: the AUG is essential since it is the actual initiation codon encoding a methionine amino acid at the N-terminus of the protein. The A nucleotide of the "AUG" is referred to as number 1. For a 'strong' consensus, the nucleotides at positions +4 (i.e. G in the consensus) and -3 (i.e. either A or G in the consensus) relative to the number 1 nucleotide must both match the consensus (there is no number 0 position). An 'adequate' consensus has only 1 of these sites, while a 'weak' consensus has neither. The cc at -1 and -2 are not as conserved, but contribute to the overall strength.[4] There is also evidence that a G in the -6 position is important in the initiation of translation.[2]
There are examples in vivo of each of these types of Kozak consensus, and they probably evolved as yet another mechanism of gene regulation. Lmx1b is an example of a gene with a weak Kozak consensus sequence.[5] For initiation of translation from such a site, other features are required in the mRNA sequence in order for the ribosome to recognize the initiation codon.
- Variations in the consensus sequence:
(gcc)gccRccAUGG
AGNNAUGN
ANNAUGG
ACCAUGG
GACACCAUGG
[edit] Mutations
Research has shown that a mutation of G—>C in the -6 position of the β-globin gene (β+45; human) disrupted the haematological and biosynthetic phenotype function. This was the first mutation found in the Kozak sequence. It was found in a family from the Southeast Italy and they suffered from thalassaemia intermedia.[2]
[edit] References
- ^ Kozak M. "An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs". Nucleic Acids Res 15 (20): 8125-48. PMID 3313277.
- ^ a b c De Angioletti M, Lacerra G, Sabato V, Carestia C (2004). (2004). "Beta+45 G --> C: a novel silent beta-thalassaemia mutation, the first in the Kozak sequence". Br J Haematol 124 (2): 224-31. PMID 14687034.
- ^ Kozak M (1984). "Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo". Nature 308: 241-246. PMID 6700727.
- ^ "Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes" (1986). Cell 44 (2): 283-92. PMID 3943125.
- ^ Dunston JA, et al. "The human LMX1B gene: transcription unit, promoter, and pathogenic mutations". Genomics 84 (3): 565-76.}}
- Kozak M (1990). "Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes".
- Kozak M (1991). "An analysis of vertebrate mRNA sequences: Intimations of translational control". J Cell Biol 115:887–903. [[1]]
[edit] See also
- Shine-Dalgarno sequence, the ribosomal binding site of prokaryotes.
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