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Translation - Advanced Douglas Wilkin, Ph.D. Say Thanks to the Authors Click http://www.ck12.org/saythanks (No sign in required) To access a customizable version of this book, as well as other interactive content, visit www.ck12.org CK-12 Foundation is a non-profit organization with a mission to reduce the cost of textbook materials for the K-12 market both in the U.S. and worldwide. Using an open-source, collaborative, and web-based compilation model, CK-12 pioneers and promotes the creation and distribution of high-quality, adaptive online textbooks that can be mixed, modified and printed (i.e., the FlexBook® textbooks). Copyright © 2017 CK-12 Foundation, www.ck12.org The names “CK-12” and “CK12” and associated logos and the terms “FlexBook®” and “FlexBook Platform®” (collectively “CK-12 Marks”) are trademarks and service marks of CK-12 Foundation and are protected by federal, state, and international laws. Any form of reproduction of this book in any format or medium, in whole or in sections must include the referral attribution link http://www.ck12.org/saythanks (placed in a visible location) in addition to the following terms. Except as otherwise noted, all CK-12 Content (including CK-12 Curriculum Material) is made available to Users in accordance with the Creative Commons Attribution-Non-Commercial 3.0 Unported (CC BY-NC 3.0) License (http://creativecommons.org/ licenses/by-nc/3.0/), as amended and updated by Creative Commons from time to time (the “CC License”), which is incorporated herein by this reference. Complete terms can be found at http://www.ck12.org/about/ terms-of-use. Printed: March 9, 2017 AUTHOR Douglas Wilkin, Ph.D. www.ck12.org C HAPTER Chapter 1. Translation - Advanced 1 Translation - Advanced Learning Objectives • Describe translation. Explain that translation is the process of ordering the amino acids into a polypeptide; translation involves changing the language of nucleotides into the language of amino acids. • Illustrate the process of translation, describing how mRNA, rRNA, and tRNA all work together to complete the process. • Discuss what happens to the polypeptide after translation. RNA to proteins. How? You must translate. To go from one language to another. Spanish to English, French to German, or nucleotides to amino acids. Which type is the translation of molecular biology? Obviously, the type of translating discussed here translates from the language of nucleotides to the language of amino acids. Translation Translation is “RNA → protein.” In other words, translation is the transfer of the genetic instructions in RNA to a protein made of amino acids. Translation uses the products of transcription, mRNA, tRNA, and rRNA, to convert the mRNA sequence into a polypeptide according to the genetic code. The mRNA moves from the nucleus to the cytoplasm to interact with a ribosome, which serves as the site of translation. Translation proceeds in three phases: initiation, elongation and termination. To understand translation, first we need to understand the ribosome. Ribosomes are composed of two subunits, a small subunit and a larger subunit. Prokaryotic subunits are named the 30S and 50S subunits; eukaryotic subunits are named the 40S and 60S subunits. During translation the tRNA molecules are literally “inside” the ribosomal subunits, as they sit on the mRNA strand. When tRNAs come to the ribosome, adjacent amino acids are brought together, allowing the ribosome to catalyze the formation of the peptide bond between amino acids. The ribosome has three tRNA binding sites: the A site, the P site, and the E site (Figure 1.1). The A site binds a tRNA with an attached amino acid. The P site contains the tRNA with the growing polypeptide chain attached, and the E site contains the tRNA that no longer has an attached amino acid. This tRNA is preparing to exit the ribosome. A single mRNA can be translated simultaneously by multiple ribosomes. FIGURE 1.1 This cartoon depicts the relative location of the E, P, and A sites within the ribosome. The A site binds a tRNA bound to an amino acid, the P site binds a tRNA bound to the polypeptide being synthesized, and the E site binds a tRNA without an attached amino acid before the tRNA exits the ribosome. 1 www.ck12.org Role of tRNA Transfer RNAs or tRNAs bring or tansfer the proper amino acid to the ribosome based on the genetic code. The anticodon at the bottom of the tRNA molecule binds to the codon on the mRNA. The codon on the mRNA is specific for an amino acid or stop codon. Stop codons do not have corresponding tRNA molecules, and signify the end of translation. The amino acid is attached to the 3’ end of the tRNA. Only one amino acid can be attached to a tRNA, based on that tRNA’s anticodon. Because there are 61 separate codons (actually 64, but three are stop codons) that can bind to anticodons, there must be 61 different tRNAs in a cell. The covalent attachment of an amino acid to the tRNA is catalyzed by enzymes called aminoacyl-tRNA syntheses through a process called aminoacylation. Aminoacyl tRNA synthetase, through aminoacylation, produces aminoacyl-tRNA molecules with an amino acid attached to their 3- ends. There is a single aminoacyl tRNA synthetase for each amino acid. This process is also known as "charging" the tRNA with the amino acid. Initiation in Prokaryotes The initiation of translation in prokaryotes involves the assembly of the ribosome and addition of the first amino acid, methionine. The 30S ribosomal subunit attaches to the mRNA. Next, the specific methionine tRNA is brought into the P. The anticodon of this tRNA will bind to the AUG (start) codon on the mRNA. This is the only time a tRNA will be brought into the P site; all successive tRNA’s will be brought to the A site as translation continues. The 50S ribosomal subunit then binds to the 30S subunit, completing the ribosome. Initiation in Eukaryotes The initiation of protein translation in eukaryotes is similar to that of prokaryotes with some minor modifications. The 5’ cap and 3’ poly(A) tail are involved in the recruitment of the ribosome. In eukaryotes the ribosome scans along the mRNA for the first start methionine codon. Translation may begin at all AUG codons, however only an in-frame AUG will produce a functional polypeptide. The tRNAs with attached amino acids are delivered to the ribosome by proteins called elongation factors (EF-Tu in bacteria, eEF-1 in eukaryotes), which aid in decoding the mRNA codon sequence. Elongation Elongation is fairly similar between prokaryotes and eukaryotes. As translation begins, the start tRNA is sitting on the AUG codon in the P site of the ribosome, so the next codon available to accept a tRNA is at the A site. Elongation proceeds after initiation with the binding of an tRNA to the A site. The next tRNA binds to the codon, bringing the appropriate amino acid to the ribosome, and a peptide bond joins between the start methionine and the next amino acid. This reaction is catalyzed by the ribosome. The new polypeptide chain is released from the initial tRNA. The entire ribosome complex moves along the mRNA, sending the first tRNA into the E site and the tRNA with the growing polypeptide into the P site. The A site is now empty and ready to accept another tRNA. The first tRNA now leaves the ribosome. The A site accepts a tRNA with an attached amino acid, a peptide bond forms between the two adjacent amino acids, and the process continues. Termination Termination of translation occurs when the ribosome comes to one of the three stop codons, for which there is no tRNA. At this point, a protein called a release factor binds to the A site. The release factor causes the addition of a water molecule to the polypeptide chain, resulting in the release of the completed chain from the tRNA and ribosome. The ribosome, release factor, and tRNAs then dissociate and translation is complete. The process of translation is summarized in Figure 1.2. 2 www.ck12.org Chapter 1. Translation - Advanced FIGURE 1.2 Summary of translation. Notice the mRNA segment within the ribosome. A tRNA anticodon binds to the appropriate codon, bringing the corresponding amino acid into the ribosome where it can be added to the growing polypeptide chain. Post-Translational Modification and Protein Folding The events following protein synthesis often include post-translational modification of the peptide chain and folding of the protein into its functional conformation. During and after synthesis, polypeptide chains often fold into secondary and then tertiary structures. These levels of organization were discussed in the Organic Compounds: Proteins (Advanced) concept. Briefly, the primary structure of the protein is the sequence of amino acids determined by the gene and mRNA. The secondary and tertiary structures are determined by interactions between the amino acids within the polypeptide (Figure 1.3). Many proteins undergo post-translational modification, allowing them to then perform their specific function. This may include the formation of disulfide bridges or attachment of any of a number of biochemical functional groups, such as phosphate groups, carbohydrates or lipids. Certain amino acids may be removed, or the polypeptide chain may be cut into two pieces. Lastly, two or more polypeptides may interact with each other, forming a functional protein with a quaternary structure. MEDIA Click image to the left or use the URL below. URL: http://www.ck12.org/flx/render/embeddedobject/184869 Summary • During translation, a protein is synthesized using the codons in mRNA as a guide. • Translation involves the interactions of the three types of RNA: mRNA, rRNA and tRNA. • After the protein is made, it must fold into its functional conformation. Review 1. 2. 3. 4. Outline the steps of translation in eukaryotes. What are the ribosomes three tRNA binding sites? How is translation related to the central dogma of molecular biology? What is protein folding? 3 www.ck12.org FIGURE 1.3 The four stages of protein folding. References 1. CK-12 Foundation. CK-12 Foundation . CC BY-NC 3.0 2. Original image by the National Human Genome Research Institute, redrawn by Mariana Ruiz Villarreal (LadyofHats) for CK-12 Foundation. CK-12 Foundation; Original image from: http://www.genome.gov/Glo ssary/index.cfm?id=200 . CC BY-NC 3.0 3. Courtesy of the National Human Genome Research Institute. http://www.genome.gov//Pages/Hyperion/DI R/VIP/Glossary/Illustration/protein.cfm . Public Domain 4