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The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start site.
Robert G. Roeder is an American biochemist. He is known as a pioneer scientist in eukaryotic transcription. He discovered three distinct nuclear RNA polymerases in 1969 and characterized many proteins involved in the regulation of transcription, including basic transcription factors and the first mammalian gene-specific activator over five decades of research. He is the recipient of the Gairdner Foundation International Award in 2000, the Albert Lasker Award for Basic Medical Research in 2003, and the Kyoto Prize in 2021. He currently serves as Arnold and Mabel Beckman Professor and Head of the Laboratory of Biochemical and Molecular Biology at The Rockefeller University.
Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.
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.
Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.
Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.
This family represents the internal ribosome entry site (IRES) of the Picornaviruses. IRES elements allow cap and end-independent translation of mRNA in the host cell. The IRES achieves this by mediating the internal initiation of translation by recruiting a ribosomal 43S pre-initiation complex directly to the initiation codon and eliminates the requirement for the eukaryotic initiation factor eIF4F.
The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.
The prokaryotic small ribosomal subunit, or 30S subunit, is the smaller subunit of the 70S ribosome found in prokaryotes. It is a complex of the 16S ribosomal RNA (rRNA) and 19 proteins. This complex is implicated in the binding of transfer RNA to messenger RNA (mRNA). The small subunit is responsible for the binding and the reading of the mRNA during translation. The small subunit, both the rRNA and its proteins, complexes with the large 50S subunit to form the 70S prokaryotic ribosome in prokaryotic cells. This 70S ribosome is then used to translate mRNA into proteins.
Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the EIF1AX gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs.
Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.
Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.
Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRNA) and covalently links the amino acids into a polypeptide chain. Ribosomes from all organisms share a highly conserved catalytic center. However, the ribosomes of eukaryotes are much larger than prokaryotic ribosomes and subject to more complex regulation and biogenesis pathways. Eukaryotic ribosomes are also known as 80S ribosomes, referring to their sedimentation coefficients in Svedberg units, because they sediment faster than the prokaryotic (70S) ribosomes. Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit (60S) according to their sedimentation coefficients. Both subunits contain dozens of ribosomal proteins arranged on a scaffold composed of ribosomal RNA (rRNA). The small subunit monitors the complementarity between tRNA anticodon and mRNA, while the large subunit catalyzes peptide bond formation.
The P-site is the second binding site for tRNA in the ribosome. The other two sites are the A-site (aminoacyl), which is the first binding site in the ribosome, and the E-site (exit), the third. During protein translation, the P-site holds the tRNA which is linked to the growing polypeptide chain. When a stop codon is reached, the peptidyl-tRNA bond of the tRNA located in the P-site is cleaved releasing the newly synthesized protein. During the translocation step of the elongation phase, the mRNA is advanced by one codon, coupled to movement of the tRNAs from the ribosomal A to P and P to E sites, catalyzed by elongation factor EF-G.
Marilyn S. Kozak is an American professor of biochemistry at the Robert Wood Johnson Medical School. She was previously at the University of Medicine and Dentistry of New Jersey before the school was merged. She was awarded a PhD in microbiology by Johns Hopkins University studying the synthesis of the Bacteriophage MS2, advised by Daniel Nathans. In her original faculty job proposal, she sought to study the mechanism of eukaryotic translation initiation, a problem long thought to have already been solved by Joan Steitz. While in the Department of Biological Sciences at University of Pittsburgh, she published a series of studies that established the scanning model of translation initiation and the Kozak consensus sequence. Her current research interests are unknown as her last publication was in 2008.
Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor. The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits.
Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.
DExH-box helicase 29 (DHX29) is a 155 kDa protein that in humans is encoded by the DHX29 gene.
Translation regulation by 5′ transcript leader cis-elements is a process in cellular translation.
References
- ↑ Sonenberg, Nahum; Hinnebusch, Alan G. (2009). "Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets". Cell. Elsevier BV. 136 (4): 731–745. doi:10.1016/j.cell.2009.01.042. ISSN 0092-8674. PMC 3610329 . PMID 19239892.
- 1 2 Aitken, Colin E.; Lorsch, Jon R. (2012). "A mechanistic overview of translation initiation in eukaryotes". Nat. Struct. Mol. Biol. 19 (6): 568–576. doi:10.1038/nsmb.2303. PMID 22664984. S2CID 9201095.
- 1 2 Fraser, Christopher S. (2015). "Quantitative studies of mRNA recruitment to the eukaryotic ribosome". Biochimie. Elsevier BV. 114: 58–71. doi:10.1016/j.biochi.2015.02.017. ISSN 0300-9084. PMC 4458453 . PMID 25742741.
- ↑ Hinnebusch, Alan G. (2017). "Structural Insights into the Mechanism of Scanning and Start Codon Recognition in Eukaryotic Translation Initiation". Trends in Biochemical Sciences. Elsevier BV. 42 (8): 589–611. doi:10.1016/j.tibs.2017.03.004. ISSN 0968-0004. PMID 28442192.
- ↑ Sokabe, Masaaki; Fraser, Christopher S. (2014-09-22). "Human Eukaryotic Initiation Factor 2 (eIF2)-GTP-Met-tRNAiTernary Complex and eIF3 Stabilize the 43 S Preinitiation Complex". Journal of Biological Chemistry. American Society for Biochemistry & Molecular Biology (ASBMB). 289 (46): 31827–31836. doi: 10.1074/jbc.m114.602870 . ISSN 0021-9258. PMC 4231660 . PMID 25246524.
- ↑ Hashem, Yaser; des Georges, Amedee; Dhote, Vidya; Langlois, Robert; Liao, Hstau Y.; Grassucci, Robert A.; Hellen, Christopher U.T.; Pestova, Tatyana V.; Frank, Joachim (2013). "Structure of the Mammalian Ribosomal 43S Preinitiation Complex Bound to the Scanning Factor DHX29". Cell. Elsevier BV. 153 (5): 1108–1119. doi:10.1016/j.cell.2013.04.036. ISSN 0092-8674. PMC 3730827 . PMID 23706745.
- ↑ Erzberger, Jan P.; Stengel, Florian; Pellarin, Riccardo; Zhang, Suyang; Schaefer, Tanja; Aylett, Christopher H.S.; Cimermančič, Peter; Boehringer, Daniel; Sali, Andrej; Aebersold, Ruedi; Ban, Nenad (2014). "Molecular Architecture of the 40S⋅eIF1⋅eIF3 Translation Initiation Complex". Cell. Elsevier BV. 158 (5): 1123–1135. doi:10.1016/j.cell.2014.07.044. ISSN 0092-8674. PMC 4151992 . PMID 25171412.
- ↑ des Georges, Amedee; Dhote, Vidya; Kuhn, Lauriane; Hellen, Christopher U. T.; Pestova, Tatyana V.; Frank, Joachim; Hashem, Yaser (2015-09-07). "Structure of mammalian eIF3 in the context of the 43S preinitiation complex". Nature. Springer Nature. 525 (7570): 491–495. Bibcode:2015Natur.525..491D. doi:10.1038/nature14891. ISSN 0028-0836. PMC 4719162 . PMID 26344199.
