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Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery.

ABSTRACT: Thioredoxins are vital components of Plasmodium proteome and act as both reducing agents and protein disulfide reductases. The malaria parasite P. falciparum thioredoxin-2 (PfTrx-2) is part of the multi-protein complex embedded within the parasite parasitophorous vacuolar membrane (PVM) which purportedly directs protein secretion. We have characterized structural and enzymatic features of PfTrx-2, and we show that PfTrx-2 adopts a canonical thioredoxin fold but with significant structural differences in its N-terminus. Our confocal localization data suggest distinct PVM residency of PfTrx-2. Based on the crystal structure of PfTrx-2, we screened and tested small molecule drug-like libraries for compounds which target unique structural features of PfTrx-2. Disruption of PfTrx-2 interactions using specific inhibitors may result in a dysfunctional parasite translocon that is rendered unable to secrete pathogenic proteins into hosts. This approach therefore offers a new focus for anti-malarial drug development.

SUBMITTER: Sharma A

PROVIDER: S-EPMC3240959 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery.

Sharma Ashwani A Sharma Arvind A Dixit Sameer S Sharma Amit A

Scientific reports 20111201

Thioredoxins are vital components of Plasmodium proteome and act as both reducing agents and protein disulfide reductases. The malaria parasite P. falciparum thioredoxin-2 (PfTrx-2) is part of the multi-protein complex embedded within the parasite parasitophorous vacuolar membrane (PVM) which purportedly directs protein secretion. We have characterized structural and enzymatic features of PfTrx-2, and we show that PfTrx-2 adopts a canonical thioredoxin fold but with significant structural differ ...[more]

PMID: 22355694

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Project description:The Clp protease system is important for maintaining proteostasis in bacteria. It consists of ClpP serine proteases and an AAA+ Clp-ATPase such as ClpC1. The hexameric ATPase ClpC1 utilizes the energy of ATP binding and hydrolysis to engage, unfold, and translocate substrates into the proteolytic chamber of homo- or hetero-tetradecameric ClpP for degradation. The assembly between the hetero-tetradecameric ClpP1P2 chamber and the Clp-ATPases containing tandem ATPase domains from the same species has not been studied in depth. Here, we present cryo-EM structures of the substrate-bound ClpC1:shClpP1P2 from Streptomyces hawaiiensis, and shClpP1P2 in complex with ADEP1, a natural compound produced by S. hawaiiensis and known to cause over-activation and dysregulation of the ClpP proteolytic core chamber. Our structures provide detailed information on the shClpP1-shClpP2, shClpP2-ClpC1, and ADEP1-shClpP1/P2 interactions, reveal conformational transition of ClpC1 during the substrate translocation, and capture a rotational ATP hydrolysis mechanism likely dominated by the D1 ATPase activity of chaperones.IMPORTANCEThe Clp-dependent proteolysis plays an important role in bacterial homeostasis and pathogenesis. The ClpP protease system is an effective drug target for antibacterial therapy. Streptomyces hawaiiensis can produce a class of potent acyldepsipeptide antibiotics such as ADEP1, which could affect the ClpP protease activity. Although S. hawaiiensis hosts one of the most intricate ClpP systems in nature, very little was known about its Clp protease mechanism and the impact of ADEP molecules on ClpP. The significance of our research is in dissecting the functional mechanism of the assembled Clp degradation machinery, as well as the interaction between ADEP1 and the ClpP proteolytic chamber, by solving high-resolution structures of the substrate-bound Clp system in S. hawaiiensis. The findings shed light on our understanding of the Clp-dependent proteolysis in bacteria, which will enhance the development of antimicrobial drugs targeting the Clp protease system, and help fighting against bacterial multidrug resistance.

Dataset Information

Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery.

Publications

Structural insights into thioredoxin-2: a component of malaria parasite protein secretion machinery.

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