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Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation

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Standard

Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation. / Banerjee, Rajat; Reynolds, Noah M; Yadavalli, Srujana S; Rice, Cory; Roy, Hervé; Banerjee, Papri; Alexander, Rebecca W; Ibba, Michael.

I: Journal of Molecular Biology, Bind 410, Nr. 2, 2011, s. 280-93.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Banerjee, R, Reynolds, NM, Yadavalli, SS, Rice, C, Roy, H, Banerjee, P, Alexander, RW & Ibba, M 2011, 'Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation', Journal of Molecular Biology, bind 410, nr. 2, s. 280-93. https://doi.org/10.1016/j.jmb.2011.05.011

APA

Banerjee, R., Reynolds, N. M., Yadavalli, S. S., Rice, C., Roy, H., Banerjee, P., Alexander, R. W., & Ibba, M. (2011). Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation. Journal of Molecular Biology, 410(2), 280-93. https://doi.org/10.1016/j.jmb.2011.05.011

Vancouver

Banerjee R, Reynolds NM, Yadavalli SS, Rice C, Roy H, Banerjee P o.a. Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation. Journal of Molecular Biology. 2011;410(2):280-93. https://doi.org/10.1016/j.jmb.2011.05.011

Author

Banerjee, Rajat ; Reynolds, Noah M ; Yadavalli, Srujana S ; Rice, Cory ; Roy, Hervé ; Banerjee, Papri ; Alexander, Rebecca W ; Ibba, Michael. / Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation. I: Journal of Molecular Biology. 2011 ; Bind 410, Nr. 2. s. 280-93.

Bibtex

@article{1db964f8a8654cfc8c1acf1089c28b16,
title = "Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation",
abstract = "Defects in organellar translation are the underlying cause of a number of mitochondrial diseases, including diabetes, deafness, encephalopathy, and other mitochondrial myopathies. The most common causes of these diseases are mutations in mitochondria-encoded tRNAs. It has recently become apparent that mutations in nuclear-encoded components of the mitochondrial translation machinery, such as aminoacyl-tRNA synthetases (aaRSs), can also lead to disease. In some cases, mutations can be directly linked to losses in enzymatic activity; however, for many, their effect is unknown. To investigate how aaRS mutations impact function without changing enzymatic activity, we chose nonsynonymous single-nucleotide polymorphisms (nsSNPs) that encode residues distal from the active site of human mitochondrial phenylalanyl-tRNA synthetase. The phenylalanyl-tRNA synthetase variants S57C and N280S both displayed wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but were less stable at low pH. Mitochondrial proteins undergo partial unfolding/refolding during import, and both S57C and N280S variants retained less activity than wild type after refolding, consistent with their reduced stability at low pH. To examine possible defects in protein folding in other aaRS nsSNPs, we compared the refolding of the human mitochondrial leucyl-tRNA synthetase variant H324Q to that of wild type. The H324Q variant had normal activity prior to unfolding, but displayed a refolding defect resulting in reduced aminoacylation compared to wild type after renaturation. These data show that nsSNPs can impact mitochondrial translation by changing a biophysical property of a protein (in this case refolding) without affecting the corresponding enzymatic activity.",
keywords = "Amino Acid Substitution, Aminoacylation, Enzyme Stability, Humans, Mitochondrial Diseases, Mitochondrial Proteins, Mutagenesis, Site-Directed, Phenylalanine-tRNA Ligase, Polymorphism, Single Nucleotide, Protein Folding, Protein Unfolding",
author = "Rajat Banerjee and Reynolds, {Noah M} and Yadavalli, {Srujana S} and Cory Rice and Herv{\'e} Roy and Papri Banerjee and Alexander, {Rebecca W} and Michael Ibba",
note = "Copyright {\textcopyright} 2011 Elsevier Ltd. All rights reserved.",
year = "2011",
doi = "10.1016/j.jmb.2011.05.011",
language = "English",
volume = "410",
pages = "280--93",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press",
number = "2",

}

RIS

TY - JOUR

T1 - Mitochondrial aminoacyl-tRNA synthetase single-nucleotide polymorphisms that lead to defects in refolding but not aminoacylation

AU - Banerjee, Rajat

AU - Reynolds, Noah M

AU - Yadavalli, Srujana S

AU - Rice, Cory

AU - Roy, Hervé

AU - Banerjee, Papri

AU - Alexander, Rebecca W

AU - Ibba, Michael

N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.

PY - 2011

Y1 - 2011

N2 - Defects in organellar translation are the underlying cause of a number of mitochondrial diseases, including diabetes, deafness, encephalopathy, and other mitochondrial myopathies. The most common causes of these diseases are mutations in mitochondria-encoded tRNAs. It has recently become apparent that mutations in nuclear-encoded components of the mitochondrial translation machinery, such as aminoacyl-tRNA synthetases (aaRSs), can also lead to disease. In some cases, mutations can be directly linked to losses in enzymatic activity; however, for many, their effect is unknown. To investigate how aaRS mutations impact function without changing enzymatic activity, we chose nonsynonymous single-nucleotide polymorphisms (nsSNPs) that encode residues distal from the active site of human mitochondrial phenylalanyl-tRNA synthetase. The phenylalanyl-tRNA synthetase variants S57C and N280S both displayed wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but were less stable at low pH. Mitochondrial proteins undergo partial unfolding/refolding during import, and both S57C and N280S variants retained less activity than wild type after refolding, consistent with their reduced stability at low pH. To examine possible defects in protein folding in other aaRS nsSNPs, we compared the refolding of the human mitochondrial leucyl-tRNA synthetase variant H324Q to that of wild type. The H324Q variant had normal activity prior to unfolding, but displayed a refolding defect resulting in reduced aminoacylation compared to wild type after renaturation. These data show that nsSNPs can impact mitochondrial translation by changing a biophysical property of a protein (in this case refolding) without affecting the corresponding enzymatic activity.

AB - Defects in organellar translation are the underlying cause of a number of mitochondrial diseases, including diabetes, deafness, encephalopathy, and other mitochondrial myopathies. The most common causes of these diseases are mutations in mitochondria-encoded tRNAs. It has recently become apparent that mutations in nuclear-encoded components of the mitochondrial translation machinery, such as aminoacyl-tRNA synthetases (aaRSs), can also lead to disease. In some cases, mutations can be directly linked to losses in enzymatic activity; however, for many, their effect is unknown. To investigate how aaRS mutations impact function without changing enzymatic activity, we chose nonsynonymous single-nucleotide polymorphisms (nsSNPs) that encode residues distal from the active site of human mitochondrial phenylalanyl-tRNA synthetase. The phenylalanyl-tRNA synthetase variants S57C and N280S both displayed wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but were less stable at low pH. Mitochondrial proteins undergo partial unfolding/refolding during import, and both S57C and N280S variants retained less activity than wild type after refolding, consistent with their reduced stability at low pH. To examine possible defects in protein folding in other aaRS nsSNPs, we compared the refolding of the human mitochondrial leucyl-tRNA synthetase variant H324Q to that of wild type. The H324Q variant had normal activity prior to unfolding, but displayed a refolding defect resulting in reduced aminoacylation compared to wild type after renaturation. These data show that nsSNPs can impact mitochondrial translation by changing a biophysical property of a protein (in this case refolding) without affecting the corresponding enzymatic activity.

KW - Amino Acid Substitution

KW - Aminoacylation

KW - Enzyme Stability

KW - Humans

KW - Mitochondrial Diseases

KW - Mitochondrial Proteins

KW - Mutagenesis, Site-Directed

KW - Phenylalanine-tRNA Ligase

KW - Polymorphism, Single Nucleotide

KW - Protein Folding

KW - Protein Unfolding

U2 - 10.1016/j.jmb.2011.05.011

DO - 10.1016/j.jmb.2011.05.011

M3 - Journal article

C2 - 21601574

VL - 410

SP - 280

EP - 293

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 2

ER -

ID: 38488939