Abstract
Rhodococcus equi is a multi-host pathogen that infects a range of animals as well as immune-compromised humans. Equine and porcine isolates harbour a virulence plasmid encoding a homologous family of virulence-associated proteins associated with the capacity of R. equi to divert the normal processes of endosomal maturation, enabling bacterial survival and proliferation in alveolar macrophages. To provide a basis for probing the function of the Vap proteins in virulence, the crystal structure of VapD was determined. VapD is a monomer as determined by multi-angle laser light scattering. The structure reveals an elliptical, compact eight-stranded β-barrel with a novel strand topology and pseudo-twofold symmetry, suggesting evolution from an ancestral dimer. Surface-associated octyl-β-D-glucoside molecules may provide clues to function. Circular-dichroism spectroscopic analysis suggests that the β-barrel structure is preceded by a natively disordered region at the N-terminus. Sequence comparisons indicate that the core folds of the other plasmid-encoded virulence-associated proteins from R. equi strains are similar to that of VapD. It is further shown that sequences encoding putative R. equi Vap-like proteins occur in diverse bacterial species. Finally, the functional implications of the structure are discussed in the light of the unique structural features of VapD and its partial structural similarity to other β-barrel proteins.
Highlights
Rhodococcus equi is a soil-borne bacterial pathogen that causes disease in a range of animals, including pigs, sheep and cattle
Having diverted the cell’s destruc- crystals of VapD suitable for structure determination; here, tion pathways, the R. equi cells begin to multiply within the we present the structure of a core fragment of VapD solved membrane-enclosed vesicle and to exert cytotoxic effects
In silico secondary-structure analysis of the sequence of the virulenceassociated proteins (Vaps) proteins predicted that the 20–50-residue variable regions following the signal peptides at their Ntermini are natively disordered, while the remainder of the chains form -strands and a single -helix (McGuffin et al, 2000)
Summary
Rhodococcus equi is a soil-borne bacterial pathogen that causes disease in a range of animals, including pigs, sheep and cattle. It is an opportunistic pathogen among immunecompromised humans such as AIDS patients, in which it causes tuberculosis-like symptoms. It is most closely associated with disease in young horses, in which it causes a severe pyogranulomatous pneumonia (Muscatello et al, 2007). It is believed that the major route of R. equi infection and disease transmission is through inhalation into the lungs of aerosolized dust formed from contaminated faeces as well as by aerosol transmission between foals (Muscatello et al, 2009). The phagosome in which R. equi resides would normally undergo a process of maturation, acquiring degradative and microbicidal properties through sequential fusion with a series of endomembrane compartments
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