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

Result code in 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>

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30303 - Infectious Diseases

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2017

Confidentiality

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

Name of the periodical

PLoS Neglected Tropical Diseases

ISSN

1935-2735

e-ISSN

—

Volume of the periodical

11

Issue of the periodical within the volume

4

Country of publishing house

US - UNITED STATES

Number of pages

21

Pages from-to

—

UT code for WoS article

000402256700069

EID of the result in the Scopus database

2-s2.0-85019162077