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Chapter 7 Using the genetic code 7.1 Introduction 7.2 Codon-anticodon recognition involves wobbling 7.3 tRNA contains modified bases that influence its pairing properties 7.4 (There are sporadic alterations of the universal code) 7.5 tRNAs are charged with amino acids by synthetases 7.6 Accuracy depends on proofreading 7.7 Suppressor tRNAs have mutated anticodons that read new codons 7.8 The accuracy of translation 7.9 tRNA may influence the reading frame 7.1 Introduction Stop codons are the three triplets (UAA, UAG, UGA) which terminate protein synthesis. 7.1 Introduction Figure 7.1 All the triplet codons have meaning: 61 represent amino acids, and 3 cause termination (STOP). 7.1 Introduction Figure 7.2 The number of codons for each amino acid does not correlate closely with its frequency of use in proteins. 7.2 Codon-anticodon recognition involves wobbling Wobble hypothesis accounts for the ability of a tRNA to recognize more than one codon by unusual (non-G C, non-A T) pairing with the third base of a codon. 7.2 Codon-anticodon recognition involves wobbling Figure 7.3 Third bases have the least influence on codon meanings. Boxes indicate groups of codons within which third-base degeneracy ensures that the meaning is the same. 7.2 Codon-anticodon recognition involves wobbling Figure 7.4 Wobble in base pairing allows G-U pairs to form between the third base of the codon and and the first base of the anticodon. 7.2 Codon-anticodon recognition involves wobbling Figure 7.5 Codon-anticodon pairing involves wobbling at the third position. 7.3 tRNA contains modified bases that influence its pairing properties Modification of DNA or RNA includes all changes made to the nucleotides after their initial incorporation into the polynucleotide chain. 7.3 tRNA contains modified bases that influence its pairing properties Figure 7.6 All of the four bases in tRNA can be modified. 7.3 tRNA contains modified bases that influence its pairing properties Figure 7.7 Modification to inosine allows pairing with U, C, and A. 7.3 tRNA contains modified bases that influence its pairing properties Figure 7.8 Modification to 2thiouridine restricts pairing to A alone because only one Hbond can form with G. 7.3 tRNA contains modified bases that influence its pairing properties Figure 7.7 Modification to inosine allows pairing with U, C, and A. 7.4 There are sporadic alterations of the universal code Figure 7.9 Changes in the genetic code in mitochondria can be traced in phylogeny. The minimum number of independent changes is generated by supposing that the AUA=Met and the AAA=Asn changes each occurred independently twice, and that the earlyAUA=Met change was reversed in echinoderms. 7.4 There are sporadic alterations of the universal code Figure 7.9 Changes in the genetic code in mitochondria can be traced in phylogeny. The minimum number of independent changes is generated by supposing that the AUA=Met and the AAA=Asn changes each occurred independently twice, and that the earlyAUA=Met change was reversed in echinoderms. 7.5 tRNAs are charged with amino acids by synthetases Cognate tRNAs are those recognized by a particular aminoacyl-tRNA synthetase. Isoaccepting tRNAs represent the same amino acid. 7.5 tRNAs are charged with amino acids by synthetases Figure 7.10 An aminoacyl-tRNA synthetase charges tRNA with an amino acid. 7.5 tRNAs are charged with amino acids by synthetases Figure 7.11 An aminoacyltRNA synthetase contains three or four regions with different functions. (Only multimeric synthetases possess an oligomerization domain.) 7.5 tRNAs are charged with amino acids by synthetases Figure 7.12 Crystal structures show that class I and class II aminoacyl-tRNA synthetases bind the opposite faces of their tRNA substrates. The tRNA is shown in red, and the protein in blue. Photographs kindly provided by Dino Moras. 7.5 tRNAs are charged with amino acids by synthetases Figure 7.13 A class I tRNA synthetase contacts tRNA at the minor groove of the acceptor stem and at the anticodon. 7.5 tRNAs are charged with amino acids by synthetases Figure 7.14 A class II aminoacyl-tRNA synthetase contacts tRNA at the major groove of the acceptor helix and at the anticodon loop. 7.6 Accuracy depends on proofreading Proofreading refers to any mechanism for correcting errors in protein or nucleic acid synthesis that involves scrutiny of individual units after they have been added to the chain. 7.6 Accuracy depends on proofreading Figure 7.15 Recognition of the correct tRNA by synthetase is controlled at two steps. First, the enzyme has a greater affinity for its cognate tRNA. Second, the aminoacylation of the incorrect tRNA is very slow. 7.6 Accuracy depends on proofreading Figure 7.16 When a synthetase binds the incorrect amino acid, proofreading requires binding of the cognate tRNA. It may take place either by a conformation change that causes hydrolysis of the incorrect aminoacyl-adenylate, or by transfer of the amino acid to RNA, following by hydrolysis. 7.6 Accuracy depends on proofreading Figure 7.17 The accuracy of charging tRNAIle by its synthetase depends on error control at two stages. 7.7 Suppressor tRNAs have mutated anticodons that read new codons Missense mutations change a single codon and so may cause the replacement of one amino acid by another in a protein sequence. Nonsense codon means a termination codon. Suppressor (extragenic) is usually a gene coding a mutant tRNA that reads the mutated codon either in the sense of the original codon or to give an acceptable substitute for the original meaning. 7.7 Suppressor tRNAs have mutated anticodons that read new codons Figure 7.18 Nonsense mutations can be suppressed by a tRNA with a mutant anticodon, which inserts an amino acid at the mutant codon, producing a full length protein in which the original Leu residue has been replaced by Tyr. 7.7 Suppressor tRNAs have mutated anticodons that read new codons Figure 7.19 Nonsense suppressor tRNAs are generated by mutations in the anticodon. 7.7 Suppressor tRNAs have mutated anticodons that read new codons Figure 7.20 Missense suppression occurs when the anticodon of tRNA is mutated so that it responds to the wrong codon. The suppression is only partial because both the wildtype tRNA and the suppressor tRNA can respond to AGA. 7.7 Suppressor tRNAs have mutated anticodons that read new codons Figure 7.21 Nonsense suppressors also read through natural termination codons, synthesizing proteins that are longer than wild-type. 7.8 The accuracy of translation ◆ 控制正确性的直接机制是将由A位点的空间化学来决定密码子-反密码 子的识别地区。核糖体的几何学决定密码子-反密码子的结合以这样的方 式进行:通过蛋白质S12,S4和S5的结构接受氨酰-tRNA使得正确性或强 或弱。(或者通过它们对rRNA结构的影响力) ◆ 正确性是核糖体运动的间接影响。核糖体的速度可以决定tRNA识别的 可能性,从而决定此过程的有效性。这个模型解释了改变链延长的动力学 可以影响链霉素。相关参数是核糖体运动速度随时间的变化决定了是结合 还是分开,如果肽链形成的速度增大,在氨酰-tRNA逃避之前,在键形成 中不正确的氨酰决定tRNA识别的可能性,从而决定此过程的有效性。这个 模型解释了改变链延长的动力学可以影响链霉素。相关参数是核糖体运动 速度随时间的变化决定了是结合还是分开,如果肽链形成的速度增大,在 氨酰-tRNA逃避之前,在键形成中不正确的氨酰tRNA更容易被诱捕。减 慢蛋白质合成的速度将会给修正。 7.8 The accuracy of translation ◆ 控制正确性的直接机制是将由A位点的空间化学来决定密码子-反密码 子的识别地区。核糖体的几何学决定密码子-反密码子的结合以这样的方 式进行:通过蛋白质S12,S4和S5的结构接受氨酰-tRNA使得正确性或强 或弱。(或者通过它们对rRNA结构的影响力) ◆ 正确性是核糖体运动的间接影响。核糖体的速度可以决定tRNA识别的 可能性,从而决定此过程的有效性。这个模型解释了改变链延长的动力学 可以影响链霉素。相关参数是核糖体运动速度随时间的变化决定了是结合 还是分开,如果肽链形成的速度增大,在氨酰-tRNA逃避之前,在键形成 中不正确的氨酰决定tRNA识别的可能性,从而决定此过程的有效性。这个 模型解释了改变链延长的动力学可以影响链霉素。相关参数是核糖体运动 速度随时间的变化决定了是结合还是分开,如果肽链形成的速度增大,在 氨酰-tRNA逃避之前,在键形成中不正确的氨酰tRNA更容易被诱捕。减 慢蛋白质合成的速度将会给修正。 7.9 tRNA may influence the reading frame Figure 7.22 A +1 frameshift is required for expression of the tyb gene of the yeast Ty element. The shift occurs at a 7 base sequence at which two Leu codon(s) are followed by a scarce Arg codon. 7.9 tRNA may influence the reading frame Figure 7.22 A +1 frameshift is required for expression of the tyb gene of the yeast Ty element. The shift occurs at a 7 base sequence at which two Leu codon(s) are followed by a scarce Arg codon. 7.10 Summary 1. The sequence of mRNA read in triplets 5 3 is related by the genetic code to the amino acid sequence of protein read from N- to C-terminus. 2. Multiple tRNAs may respond to a particular codon. 3. Each amino acid is recognized by a particular aminoacyl-tRNA synthetase, which also recognizes all of the tRNAs coding for that amino acid. 7.10 Summary 4. Aminoacyl-tRNA synthetases vary widely, but fall into two general groups according to the structure of the catalytic domain. 5. Mutations may allow a tRNA to read different codons; the most common form of such mutations occurs in the anticodon itself. 6. Frameshifts of the +1 type may be caused by aberrant tRNAs that read "codons" of 4 bases.