Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F22%3A00551535" target="_blank" >RIV/86652036:_____/22:00551535 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/22:10436196 RIV/00064165:_____/22:10436196

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0006291X21016971?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0006291X21016971?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbrc.2021.12.062" target="_blank" >10.1016/j.bbrc.2021.12.062</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX

Popis výsledku v původním jazyce

Variegate porphyria is caused by mutations in the protoporphyrinogen oxidase IX (PPOX, EC 1.3.3.4) gene, resulting in reduced overall enzymatic activity of PPOX in human tissues. Recently, we have identified the His333Arg mutation in the PPOX protein (PPOX(H333R)) as a putative founder mutation in the Moroccan Jewish population. Herein we report the molecular characterization of PPOX(H333R) in vitro and in cells. Purified recombinant PPOX(H333R) did not show any appreciable enzymatic activity in vitro, corroborating the clinical findings. Biophysical experiments and molecular modeling revealed that PPOX(H333R) is not folded properly and fails to adopt its native functional three-dimensional conformation due to steric clashes in the vicinity of the active site of the enzyme. On the other hand, PPOX(H333R) subcellular distribution, as evaluated by live-cell confocal microscopy, is unimpaired suggesting that the functional three-dimensional fold is not required for efficient transport of the polypeptide chain into mitochondria. Overall, the data presented here provide molecular underpinnings of the pathogenicity of PPOX(H333R) and might serve as a blueprint for deciphering whether a given PPOX variant represents a disease-causing mutation. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Název v anglickém jazyce

Molecular characterization of a novel His333Arg variant of human protoporphyrinogen oxidase IX

Popis výsledku anglicky

Variegate porphyria is caused by mutations in the protoporphyrinogen oxidase IX (PPOX, EC 1.3.3.4) gene, resulting in reduced overall enzymatic activity of PPOX in human tissues. Recently, we have identified the His333Arg mutation in the PPOX protein (PPOX(H333R)) as a putative founder mutation in the Moroccan Jewish population. Herein we report the molecular characterization of PPOX(H333R) in vitro and in cells. Purified recombinant PPOX(H333R) did not show any appreciable enzymatic activity in vitro, corroborating the clinical findings. Biophysical experiments and molecular modeling revealed that PPOX(H333R) is not folded properly and fails to adopt its native functional three-dimensional conformation due to steric clashes in the vicinity of the active site of the enzyme. On the other hand, PPOX(H333R) subcellular distribution, as evaluated by live-cell confocal microscopy, is unimpaired suggesting that the functional three-dimensional fold is not required for efficient transport of the polypeptide chain into mitochondria. Overall, the data presented here provide molecular underpinnings of the pathogenicity of PPOX(H333R) and might serve as a blueprint for deciphering whether a given PPOX variant represents a disease-causing mutation. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10610 - Biophysics

Projekt

<a href="/cs/project/NV17-32727A" target="_blank" >NV17-32727A: Inovativní strategie pro personalizovanou medicínu: molekulární přístupy cílené na vliv dědičných metabolických chorob způsobených mutacemi v PPO</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

Biochemical and Biophysical Research Communications

ISSN

0006-291X

e-ISSN

1090-2104

Svazek periodika

588

Číslo periodika v rámci svazku

JAN 15 2022

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

182-186

Kód UT WoS článku

000737460100002

EID výsledku v databázi Scopus

2-s2.0-85121769489