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Ch. 14 - Translation and Proteins
Klug - Concepts of Genetics 12th Edition
Klug12th EditionConcepts of GeneticsISBN: 9780135564776당신이 사용하는 게 아니라요?교과서 변경
모든 교과서Klug 12th EditionCh. 14 - Translation and Proteins문제 37b
14장, 문제 37b

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.
Which mutation would you predict has a more severe impairment of translation in mitochondria, and why?

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Understand the structure and function of the mtAlaRS enzyme: The mitochondrial alanyl-tRNA synthetase (mtAlaRS) enzyme has two key domains. The N-terminal domain (amino acids 36–481) is responsible for catalyzing tRNA aminoacylation, which is the process of attaching the correct amino acid (alanine) to its corresponding tRNA. The internal editing domain (amino acids 484–782) ensures fidelity by catalyzing deacylation if the tRNA is charged with the wrong amino acid.
Analyze the location of the mutations: The p.Leu155Arg mutation occurs within the N-terminal domain, which is directly involved in the aminoacylation process. The p.Arg592Trp mutation occurs within the internal editing domain, which is responsible for correcting errors in amino acid attachment.
Predict the functional impact of the p.Leu155Arg mutation: Since this mutation is located in the N-terminal domain, it is likely to impair the enzyme's ability to catalyze the aminoacylation of tRNA. This would directly disrupt the attachment of alanine to its tRNA, leading to a severe impairment of mitochondrial translation.
Predict the functional impact of the p.Arg592Trp mutation: This mutation is located in the internal editing domain, which is responsible for error correction. While this mutation may reduce the enzyme's ability to correct errors, it does not directly affect the aminoacylation process. Therefore, its impact on mitochondrial translation may be less severe compared to the p.Leu155Arg mutation.
Conclude which mutation has a more severe impact: Based on the functional roles of the two domains, the p.Leu155Arg mutation in the N-terminal domain is predicted to have a more severe impairment of mitochondrial translation because it directly disrupts the aminoacylation process, which is essential for protein synthesis in mitochondria.

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Mitochondrial Function and Translation

Mitochondria are essential organelles responsible for energy production and play a critical role in protein synthesis. They contain their own genetic material and machinery for translating mitochondrial genes. The process of translation in mitochondria involves the charging of tRNA with specific amino acids, which is crucial for synthesizing mitochondrial proteins. Any dysfunction in this process can lead to severe cellular consequences, particularly in energy-demanding tissues like the heart.
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가이드 코스
08:26
Functional Genomics

Aminoacyl-tRNA Synthetase (AlaRS) Function

Aminoacyl-tRNA synthetases are enzymes that attach the correct amino acid to its corresponding tRNA, a process vital for accurate protein synthesis. The mitochondrial alanyl-tRNA synthetase (mtAlaRS) specifically charges tRNA with alanine, ensuring that proteins are synthesized correctly. Mutations in this enzyme can disrupt its function, leading to mischarged tRNAs and impaired translation, which can have severe effects on mitochondrial protein production and overall cellular function.
추천 영상:
가이드 코스
08:26
Functional Genomics

Impact of Specific Mutations on Protein Function

Mutations in genes can lead to changes in the amino acid sequence of proteins, potentially altering their structure and function. The severity of a mutation's impact often depends on its location and the nature of the amino acid change. For instance, a mutation that changes a hydrophobic amino acid to a charged one may disrupt protein folding or function more severely than a conservative substitution. Understanding the specific mutations in mtAlaRS and their effects on enzyme activity is crucial for predicting the severity of translation impairment.
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가이드 코스
05:05
Proteins
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교과서 질문

The flow of genetic information from DNA to protein is mediated by messenger RNA. If you introduce short DNA strands (called antisense oligonucleotides) that are complementary to mRNAs, hydrogen bonding may occur and 'label' the DNA/RNA hybrid for ribonuclease-H degradation of the RNA. One study [Lloyd et al. (2001). Nucl. Acids Res. 29:3664–3673] compared the effect of different-length antisense oligonucleotides upon ribonuclease-H–mediated degradation of tumor necrosis factor (TNFα) mRNA. TNFα exhibits antitumor and pro-inflammatory activities. The following graph indicates the efficacy of various-sized antisense oligonucleotides in causing ribonuclease-H cleavage. What factors other than oligonucleotide length are likely to influence antisense efficacy in vivo?

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교과서 질문

The flow of genetic information from DNA to protein is mediated by messenger RNA. If you introduce short DNA strands (called antisense oligonucleotides) that are complementary to mRNAs, hydrogen bonding may occur and 'label' the DNA/RNA hybrid for ribonuclease-H degradation of the RNA. One study [Lloyd et al. (2001). Nucl. Acids Res. 29:3664–3673] compared the effect of different-length antisense oligonucleotides upon ribonuclease-H–mediated degradation of tumor necrosis factor (TNFα) mRNA. TNFα exhibits antitumor and pro-inflammatory activities. The following graph indicates the efficacy of various-sized antisense oligonucleotides in causing ribonuclease-H cleavage. What general conclusion can be drawn from the graph?

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교과서 질문

Infantile cardiomyopathy is a devastating disorder that is fatal during the first year of life due to defects in the function of heart muscles resulting from mitochondrial dysfunction. A study, performed by Götz et al. [(2011). Am. J. Hum. Genet. 88:635–642), identified two different causative mutations in the gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS). One mutation changes a leucine residue at amino acid position 155 to arginine (p.Leu155Arg). The other mutation changes arginine at position 592 to tryptophan (p.Arg592Trp). The mtAlaRS enzyme has an N-terminal domain (amino acids 36–481) that catalyzes tRNA aminoacylation and an internal editing domain (amino acids 484–782) that catalyzes deacylation in the case that the tRNA is charged with the wrong amino acid.

Consider the position of the disease causing missense mutations in the mtAlaRS gene in the context of the known protein domains of this enzyme. What predictions can you make about how these mutations impair protein synthesis within mitochondria in different ways?

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