Kozak consensus sequence

[7] While initially limited to a subset of vertebrates (i.e. human, cow, cat, dog, chicken, guinea pig, hamster, mouse, pig, rabbit, sheep, and Xenopus), subsequent studies confirmed its conservation in higher eukaryotes generally.

[1] The sequence was defined as 5'-(gcc)gccRccAUGG-3' (IUPAC nucleobase notation summarized here) where:[7] The AUG is the initiation codon encoding a methionine amino acid at the N-terminus of the protein.

Kozak sequence strength refers to the favorability of initiation, affecting how much protein is synthesized from a given mRNA.

[4][9] The A nucleotide of the "AUG" is delineated as +1 in mRNA sequences with the preceding base being labeled as −1, i.e. there is no 0 position.

This recruitment to the m7G 5′ cap is supported by the inability of eukaryotic ribosomes to translate circular mRNA, which has no 5′ end.

[19] Upon base pairing to the start codon the eIF5 in the PIC helps to hydrolyze a guanosine triphosphate (GTP) bound to the eIF2.

In contrast, scanning along the mRNA results in a more rigorous selection process for the AUG codon than in bacteria.

[29][30] 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.

[4] Similar observations were made regarding mutations in the position −5 from the start codon, AUG. Cytosine in this position, as opposed to thymine, showed more efficient translation and increased expression of the platelet adhesion receptor, glycoprotein Ibα in humans.

[34] When the guanosine at the -6 position in the Kozak sequence of GATA4 is mutated to a cytosine, a reduction in GATA4 protein levels results, which leads to a decrease in the expression of genes regulated by the GATA4 transcription factor and linked to the development of atrial septal defect.

[35] The ability of the Kozak sequence to optimize translation can result in novel initiation codons in the typically untranslated region of the 5′ (5′ UTR) end of the mRNA transcript.

A G to A mutation was described by Bohlen et al. (2017) in a Kozak-like region in the SOX9 gene that created a new translation initiation codon in an out-of-frame open reading frame.

The patient in whom this mutation was detected had developed acampomelic campomelic dysplasia, a developmental disorder that causes skeletal, reproductive and airway issues due to insufficient SOX9 expression.

A sequence logo showing the most conserved bases around the initiation codon from over 10 000 human mRNAs . Larger letters indicate a higher frequency of incorporation. Note the larger size of A and G at the 8 position (−3, Kozak position) and at the G at position 14 which corresponds to (+4) position in the Kozak sequence.
An overview of eukaryotic initiation showing the formation of the PIC and the scanning method of initiation.
Campomelic dysplasia, a disorder that results in skeletal, reproductive and/or airway issues. [ 31 ] Campomelic dysplasia can be the result of a Kozak-related mutation in the SOX9 gene. [ 32 ]