Kozak consensus sequence

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'.cite journal |author=Kozak M |title=An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs |journal=Nucleic Acids Res. |volume=15 |issue=20 |pages=8125–48 |year=1987 |month=Oct |pmid=3313277 |pmc=306349 |doi= |url=http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3313277] The Kozak consensus sequence plays a major role in the initiation of translation process.cite journal |author=De Angioletti M, Lacerra G, Sabato V, Carestia C |title=Beta+45 G --> C: a novel silent beta-thalassaemia mutation, the first in the Kozak sequence |journal=Br J Haematol |volume=124 |issue=2 |pages=224–31 |year=2004 |pmid=14687034 |doi=10.1046/j.1365-2141.2003.04754.x]

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.cite journal |author=Kozak M |title=Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo |journal=Nature |volume=308 |pages=241–246 |year=1984 |url=http://www.nature.com/nature/journal/v308/n5956/abs/308241a0.html |pmid=6700727 |doi=10.1038/308241a0] 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.cite journal |author=Kozak M |title=Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes |journal=Cell |volume=44 |issue=2 |pages=283–92 |year=1986 |url=http://www.nature.com/nature/journal/v308/n5956/abs/308241a0.html |pmid=3943125 |doi=10.1016/0092-8674(86)90762-2] There is also evidence that a G in the -6 position is important in the initiation of translation.

There are examples in vivo of each of these types of Kozak consensus, and they probably evolved as yet another mechanism of gene regulation. [http://www.genecards.org/cgi-bin/carddisp.pl?gene=LMX1B Lmx1b] is an example of a gene with a weak Kozak consensus sequence.cite journal |author=Dunston JA, Hamlington JD, Zaveri J, "et al" |title=The human LMX1B gene: transcription unit, promoter, and pathogenic mutations |journal=Genomics |volume=84 |issue=3 |pages=565–76 |year=2004 |month=Sep |pmid=15498463 |doi=10.1016/j.ygeno.2004.06.002 |url=] 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.

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.

Variations in the consensus sequence

(gcc)gccRccAUGG AGNNAUGN ANNAUGG ACCAUGG GACACCAUGG

References

*cite journal |author=Kozak M |title=Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue=21 |pages=8301–5 |year=1990 |month=Nov |pmid=2236042 |pmc=54943 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2236042
*cite journal |author=Kozak M |title=An analysis of vertebrate mRNA sequences: intimations of translational control |journal=J. Cell Biol. |volume=115 |issue=4 |pages=887–903 |year=1991 |month=Nov |pmid=1955461 |pmc=2289952 |doi= |url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=1955461
*cite journal |author=Kozak M |title=An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs |journal=Nucleic Acids Res. |volume=15 |issue=20 |pages=8125–48 |year=1987 |month=Oct |pmid=3313277 |pmc=306349 |doi= |url=http://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3313277
*cite journal |author=Kozak M |title=Pushing the limits of the scanning mechanism for initiation of translation |journal=Gene |volume=299 |issue=1-2 |pages=1–34 |year=2002 |month=Oct |pmid=12459250 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0378111902010569

ee also

*Shine-Dalgarno sequence, the ribosomal binding site of prokaryotes.