ThANKs for the repeat

Voth, Daniel E.

doi:10.4161/cl.1.4.18738

Cited by 29 publications

(24 citation statements)

References 50 publications

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“…Indeed, these repeating motifs are one of the most common protein domains involved in protein:protein interactions. Recent reports have demonstrated that such ankyrin motifs are also found in bacterial proteins, and in particular those from intracellular pathogens (Voth, 2011). Not surprisingly, both FdtF and QdtF are found in intracellular pathogens, S. enterica O60 and P. alcalifaciens O40, respectively.…”

Section: Discussionmentioning

confidence: 99%

Molecular architecture of an N-formyltransferase from Salmonella enterica O60

Woodford

Thoden

Holden

2017

Journal of Structural Biology

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N-formylated sugars are found on the lipopolysaccharides of various pathogenic Gram negative bacteria including Campylobacter jejuni 81116, Francisella tularensis, Providencia alcalifaciens O30, and Providencia alcalifaciens O40. The last step in the biosynthetic pathways for these unusual sugars is catalyzed by N-formyltransferases that utilize N10-formyltetrahydrofolate as the carbon source. The substrates are dTDP-linked amino sugars with the functional groups installed at either the C-3′ or C-4′ positions of the pyranosyl rings. Here we describe a structural and enzymological investigation of the putative N-formyltransferase, FdtF, from Salmonella enterica O60. In keeping with its proposed role in the organism, the kinetic data reveal that the enzyme is more active with dTDP-3-amino-3,6-dideoxy-D-galactose than with dTDP-3-amino-3,6-dideoxy-D-glucose. The structural data demonstrate that the enzyme contains, in addition to the canonical N-formyltransferase fold, an ankyrin repeat moiety that houses a second dTDP-sugar binding pocket. This is only the second time an ankyrin repeat has been shown to be involved in small molecule binding. The research described herein represents the first structural analysis of a sugar N-formyltransferase that specifically functions on dTDP-3-amino-3,6-dideoxy-D-galactose in vivo and thus adds to our understanding of these intriguing enzymes.

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Section: Discussionmentioning

confidence: 99%

Molecular architecture of an N-formyltransferase from Salmonella enterica O60

Woodford

Thoden

Holden

2017

Journal of Structural Biology

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“…Anks are encoded within the genomes of many intracellular bacterial species (Pan et al ., 2008, Voth, 2011, Kaur et al ., 2012) , with amoeba-associated species tending to be enriched with Ank genes (Schmitz-Esser et al ., 2010) . Anks are variably encoded across Rickettsia genomes (Gillespie et al ., 2008, Merhej & Raoult, 2011) , with larger genomes indicative of high rates of lateral gene transfer, namely R .…”

Section: Secretory Proteins At the Host Interfacementioning

confidence: 99%

Secretome of obligate intracellularRickettsia

et al. 2014

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The genus Rickettsia (Alphaproteobacteria; Rickettsiales; Rickettsiaceae) is comprised of obligate intracellular parasites, with virulent species of interest both as causes of emerging infectious diseases and for their potential deployment as bioterrorism agents. Currently there are no effective commercially available vaccines, with treatment limited primarily to tetracycline antibiotics, though others (e.g., josamycin, ciprofloxacin, chloramphenicol and azithromycin) are also effective. Much of the recent research geared towards understanding mechanisms underlying rickettsial pathogenicity has centered on characterization of secreted proteins that directly engage eukaryotic cells. Herein, we review all aspects of the Rickettsia secretome, including six secretion systems, 19 characterized secretory proteins, and potential moonlighting proteins identified on surfaces of multiple Rickettsia species. Employing bioinformatics and phylogenomics, we present novel structural and functional insight on each secretion system. Unexpectedly, our investigation revealed that the majority of characterized secretory proteins have not been assigned to their cognate secretion pathways. Furthermore, for most secretion pathways, the requisite signal sequences mediating translocation are poorly understood. As a blueprint for all known routes of protein translocation into host cells, this resource will assist research aimed at uniting characterized secreted proteins with their apposite secretion pathways. Furthermore, our work will help in the identification of novel secreted proteins involved in rickettsial “life on the inside”.

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“…Ankyrin repeat-containing proteins (Anks) are emerging as key virulence factors of intracellular bacteria and viruses for interacting with host cell proteins to coopt cellular processes (27). O. tsutsugamushi encodes one of the largest known Ank repertoires of any microbe (26).…”

mentioning

confidence: 99%

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

et al. 2018

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Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens 1 billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection but its growth becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins. Here, we show that O. tsutsugamushi invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. O. tsutsugamushi also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an O. tsutsugamushi growth defect at 72 h that can be rescued by amino acid supplementation. Thus, O. tsutsugamushi temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The O. tsutsugamushi effector Ank4 is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by O. tsutsugamushi during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy O. tsutsugamushi infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements.

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ThANKs for the repeat

Cited by 29 publications

References 50 publications

Molecular architecture of an N-formyltransferase from Salmonella enterica O60

Molecular architecture of an N-formyltransferase from Salmonella enterica O60

Secretome of obligate intracellularRickettsia

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

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