page_title: Kozak consensus sequence
section_title: Ribosome assembly
hierarchical_section_title: Kozak consensus sequence / Ribosome assembly
caption_attribution_description: English: The scheme of cap-dependent eukaryotic translation initiation mechanism 中文（简体）‎: Cap依赖的真核翻译起始机制简图
context_page_description: The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.
  The Kozak sequence is not to be confused with the ribosomal binding site, that being either the 5′ cap of a messenger RNA or an internal ribosome entry site.
context_section_description: The ribosome assembles on the start codon (AUG), located within the Kozak sequence. Prior to translation initiation, scanning is done by the pre-initiation complex (PIC). The PIC consists of the 40S (small ribosomal subunit) bound the to ternary complex, eIF2-GTP-intiatorMet tRNA (TC) to form the 43S ribosome. Assisted by several other initiation factors (eIF1 and eIF1A, eIF5, eIF3, polyA binding protein) it is recruited to the 5′ end of the mRNA.  Eukaryotic mRNA is capped with a 7-methylguanosine (m7G) nucleotide which can helps recruit the PIC to the mRNA and initiate scanning.  This recruitment to the m7G 5′ cap is support by the inability of eukaryotic ribosomes to translate circular mRNA, which has no 5′ end.  Once the PIC binds to the mRNA it scans until it reaches the first AUG codon in a Kozak sequence. This scanning is referred to as the scanning mechanism of initiation.
  The scanning mechanism of Initiation starts when the PIC binds the 5′ end of the mRNA.  Scanning is stimulated by Dhx29 and Ddx3/Ded1 and eIF4 proteins. The Dhx29 and Ddx3/Ded1 are DEAD-box helicases that help to unwind any secondary mRNA structure which could hinder scanning.  The scanning of an mRNA continues until the first AUG codon on the mRNA is reached, this is known as the "First AUG Rule".  While exceptions to the "First AUG Rule" exist, most exceptions take place at a second AUG codon that is located 3 to 5 nucleotides downstream from the first AUG, or within 10 nucleotides from the 5′ end of the mRNA. At the AUG codon a Methionine tRNA anticodon is recognized by mRNA codon. Upon base pairing to the start codon the eIF5 in the PIC helps to hydrolyze a guanosine triphosphate (GTP) bound to the eIF2.  This leads to the a structural rearrangement that commits the PIC to binding to the large ribosomal subunit (60S) and forming the ribosomal complex (80S).  Once the 80S ribosome complex is formed then the elongation phase of translation starts.
  The first start codon closest to the 5′ end of the strand is not always recognized if it is not contained in a Kozak-like sequence. Lmx1b is an example of a gene with a weak Kozak consensus sequence. 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. Exceptions to the first AUG rule may occur if it is not contained in a Kozak-like sequence. This is called leaky scanning and could be a potential way to control translation through initiation. 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.
  It is believed that the PIC is stalled at the Kozak sequence by interactions between eIF2 and the −3 and +4 nucleotides in the Kozak position. This stalling allows the start codon and the corresponding anticodon time to form the correct hydrogen bonding. The Kozak consensus sequence is so common that the similarity of the sequence around the AUG codon to the Kozak Sequence is used as a criterion for finding start codons in eukaryotes.
caption: An overview of eukaryotic initiation showing the formation of the PIC and the scanning method of initiation.
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