Trypanosoma brucei TbIF1 inhibits the essential F<inf>1</inf>-ATPase in the infectious form of the parasite

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F17%3A00479560" target="_blank" >RIV/60077344:_____/17:00479560 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1371/journal.pntd.0005552" target="_blank" >http://dx.doi.org/10.1371/journal.pntd.0005552</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1371/journal.pntd.0005552" target="_blank" >10.1371/journal.pntd.0005552</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Trypanosoma brucei TbIF1 inhibits the essential F<inf>1</inf>-ATPase in the infectious form of the parasite

Popis výsledku v původním jazyce

The mitochondrial (mt) F o F 1ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF), but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF), which lacks a canonical respiratory chain. This unconventional dependence on F o F 1ATPase is required to maintain the essential mt membrane potential (Δψm). Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool. To protect against this cellular treason, the highly conserved inhibitory factor 1 (IF1) binds the enzyme in a manner that solely inhibits the hydrolytic activity. Intriguingly, we were able to identify the IF1 homolog in T. brucei (TbIF1), but determined that its expression in the mitochondrion is tightly regulated throughout the life cycle as it is only detected in PF cells. TbIF1 appears to primarily function as an emergency brake in PF cells, where it prevented the restoration of the Δψm by F o F 1ATPase when respiration was chemically inhibited. In vitro, TbIF1 overexpression specifically inhibits the hydrolytic activity but not the synthetic capability of the F o F 1ATP synthase in PF mitochondria. Furthermore, low μM amounts of recombinant TbIF1 achieve the same inhibition of total mt ATPase activity as the F o F 1ATPase specific inhibitors, azide and oligomycin. Therefore, even minimal ectopic expression of TbIF1 in BF cells proved lethal as the indispensable Δψm collapsed due to inhibited F o F 1ATPase. In summary, we provide evidence that T. brucei harbors a natural and potent unidirectional inhibitor of the vital F o F 1ATPase activity that can be exploited for future structure-based drug design.

Název v anglickém jazyce

Trypanosoma brucei TbIF1 inhibits the essential F<inf>1</inf>-ATPase in the infectious form of the parasite

Popis výsledku anglicky

The mitochondrial (mt) F o F 1ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF), but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF), which lacks a canonical respiratory chain. This unconventional dependence on F o F 1ATPase is required to maintain the essential mt membrane potential (Δψm). Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool. To protect against this cellular treason, the highly conserved inhibitory factor 1 (IF1) binds the enzyme in a manner that solely inhibits the hydrolytic activity. Intriguingly, we were able to identify the IF1 homolog in T. brucei (TbIF1), but determined that its expression in the mitochondrion is tightly regulated throughout the life cycle as it is only detected in PF cells. TbIF1 appears to primarily function as an emergency brake in PF cells, where it prevented the restoration of the Δψm by F o F 1ATPase when respiration was chemically inhibited. In vitro, TbIF1 overexpression specifically inhibits the hydrolytic activity but not the synthetic capability of the F o F 1ATP synthase in PF mitochondria. Furthermore, low μM amounts of recombinant TbIF1 achieve the same inhibition of total mt ATPase activity as the F o F 1ATPase specific inhibitors, azide and oligomycin. Therefore, even minimal ectopic expression of TbIF1 in BF cells proved lethal as the indispensable Δψm collapsed due to inhibited F o F 1ATPase. In summary, we provide evidence that T. brucei harbors a natural and potent unidirectional inhibitor of the vital F o F 1ATPase activity that can be exploited for future structure-based drug design.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30303 - Infectious Diseases

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

2017

Kód důvěrnosti údajů

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

Název periodika

PLoS Neglected Tropical Diseases

ISSN

1935-2735

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

21

Strana od-do

—

Kód UT WoS článku

000402256700069

EID výsledku v databázi Scopus

2-s2.0-85019162077