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Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site
P. Man, M. Fábry, I. Sieglová, D. Kavan, P. Novák, A. Hnízda,
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- deoxyguaninnukleotidy chemie MeSH
- katalytická doména MeSH
- mutace MeSH
- mutageneze cílená MeSH
- pyrofosfatasy chemie genetika MeSH
- stabilita proteinů MeSH
- teplota MeSH
- thermolysin chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Germline mutations in NUDT15 cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V18I mutants using thermolysin-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature. This structural perturbation is shared by the mutations despite their different positions within the protein structure. Reaction products of NUDT15 reverted these conformational abnormalities, demonstrating the importance of ligands for stabilization of a native state of the mutants. This study shows the action of pharmacogenetic variants in NUDT15 in a context of protein structure, which might open novel directions in personalized chemotherapy.
Citace poskytuje Crossref.org
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- $a Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site / $c P. Man, M. Fábry, I. Sieglová, D. Kavan, P. Novák, A. Hnízda,
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- $a Germline mutations in NUDT15 cause thiopurine intolerance during treatment of leukemia or autoimmune diseases. Previously, it has been shown that the mutations affect the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo. Here we provide structural insights into protein destabilization in R139C and V18I mutants using thermolysin-based proteolysis and H/D exchange followed by mass spectrometry. Both mutants exhibited destabilization of the catalytic site, which was more pronounced at higher temperature. This structural perturbation is shared by the mutations despite their different positions within the protein structure. Reaction products of NUDT15 reverted these conformational abnormalities, demonstrating the importance of ligands for stabilization of a native state of the mutants. This study shows the action of pharmacogenetic variants in NUDT15 in a context of protein structure, which might open novel directions in personalized chemotherapy.
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