Trypanosoma brucei TbIF1 inhibits the essential F-1-ATPase in the infectious form of the parasite

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60076658%3A12310%2F17%3A43895540" target="_blank" >RIV/60076658:12310/17:43895540 - isvavai.cz</a>

Result on the web

<a href="http://journals.plos.org/plosntds/article/authors?id=10.1371/journal.pntd.0005552" target="_blank" >http://journals.plos.org/plosntds/article/authors?id=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-1-ATPase in the infectious form of the parasite

Original language description

The mitochondrial (mt) FoF1-ATP 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 FoF1-ATPase is required to maintain the essential mt membrane potential (Delta psi m). 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 Delta psi m by FoF1-ATPase when respiration was chemically inhibited. In vitro, TbIF1 overexpression specifically inhibits the hydrolytic activity but not the synthetic capability of the FoF1-ATP synthase in PF mitochondria. Furthermore, low mu M amounts of recombinant TbIF1 achieve the same inhibition of total mt ATPase activity as the FoF1-ATPase specific inhibitors, azide and oligomycin. Therefore, even minimal ectopic expression of TbIF1 in BF cells proved lethal as the indispensable Delta psi m collapsed due to inhibited FoF1-ATPase. In summary, we provide evidence that T. brucei harbors a natural and potent unidirectional inhibitor of the vital FoF1-ATPase activity that can be exploited for future structure-based drug design.

Czech name

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Czech description

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Type

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

CEP classification

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OECD FORD branch

30310 - Parasitology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

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

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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

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UT code for WoS article

000402256700069

EID of the result in the Scopus database

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