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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00503803" target="_blank" >RIV/61388963:_____/19:00503803 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388971:_____/19:00508147 RIV/68378050:_____/19:00508147 RIV/00216208:11310/19:10402857

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/abs/pii/S1570963919300081?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S1570963919300081?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbapap.2019.01.006" target="_blank" >10.1016/j.bbapap.2019.01.006</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochimica Et Biophysica Acta-Proteins and Proteomics

ISSN

1570-9639

e-ISSN

—

Svazek periodika

1867

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

6

Strana od-do

376-381

Kód UT WoS článku

000461529700003

EID výsledku v databázi Scopus

2-s2.0-85060241866