Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1867, Issue 4, Pages 376-381Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbapap.2019.01.006
Keywords
Pharmacogenomic variants; Thiopurine metabolism; H/D exchange; Structural mass spectrometry; NUDT15
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Funding
- Ministry of Education of the Czech Republic (program NPU I) [LO1304]
- Ministry of Education of the Czech Republic (program InterBioMed) [LO1302]
- Academy of Sciences of the Czech Republic [RVO 61388963, 68378050]
- ERDF [CZ.1.05/1.1.00/02.0109]
- MEYS, Czechia project [LM2015043 CIISB]
- NPU II [LQ1604]
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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 V181 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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