Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site

0503803 - ÚOCHB 2020 RIV NL eng J - Článek v odborném periodiku
Man, P. - Fábry, M. - Sieglová, Irena - Kavan, D. - Novák, P. - Hnízda, Aleš
Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site.
Biochimica Et Biophysica Acta-Proteins and Proteomics. Roč. 1867, č. 4 (2019), s. 376-381. ISSN 1570-9639. E-ISSN 1878-1454
Grant CEP: GA MŠMT(CZ) LO1304; GA MŠMT LO1302
Institucionální podpora: RVO:61388963
Klíčová slova: pharmacogenomic variants * thiopurine metabolism * H/D exchange * structural mass spectrometry * NUDT15
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 2.371, rok: 2019
Způsob publikování: Omezený přístup
https://www.sciencedirect.com/science/article/abs/pii/S1570963919300081?via%3Dihub

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.
Trvalý link: http://hdl.handle.net/11104/0296721