Abstract
Candida glabrata is an opportunistic pathogenic yeast frequently causing infections in humans. Though it lacks typical virulence factors such as hyphal development, C. glabrata contains a remarkably large and diverse set of putative wall adhesins that is crucial for its success as pathogen. Here, we present an analysis of putative adhesins from the homology clusters V and VI. First, sequence similarity network analysis revealed relationships between cluster V and VI adhesins and S. cerevisiae haze protective factors (Hpf). Crystal structures of A-regions from cluster VI adhesins Awp1 and Awp3b reveal a parallel right-handed β-helix domain that is linked to a C-terminal β-sandwich. Structure solution of the A-region of Awp3b via single wavelength anomalous diffraction phasing revealed the largest known lanthanide cluster with 21 Gd3+ ions. Awp1-A and Awp3b-A show structural similarity to pectate lyases but binding to neither carbohydrates nor Ca2+ was observed. Phenotypic analysis of awp1Δ, awp3Δ, and awp1,3Δ double mutants did also not confirm their role as adhesins. In contrast, deletion mutants of the cluster V adhesin Awp2 in the hyperadhesive clinical isolate PEU382 demonstrated its importance for adhesion to polystyrene or glass, biofilm formation, cell aggregation and other cell surface-related phenotypes. Together with cluster III and VII adhesins our study shows that C. glabrata CBS138 can rely on a set of 42 Awp1-related adhesins with β-helix/α-crystallin domain architecture for modifying the surface characteristics of its cell wall.
Highlights
The yeast Candida glabrata is an opportunistic human pathogen that can cause mucosal, bloodstream, and medical device-related infections [1,2]
Together with cluster III and VII adhesins our study shows that C. glabrata CBS138 can rely on a set of 42 Awp1-related adhesins with β-helix/α-crystallin domain architecture for modifying the surface characteristics of its cell wall
These adhesins commonly present an N-terminal module consisting of a right-handed β-helix and an α-crystallin domain on the yeast surface and use a calcium-independent mode for adhesion. Their sheer number contrasts to the 20 members of the well characterized Epa and 7 members of the Pwp family of surface proteins. Given these findings we suggest that C. glabrata utilizes just two structurally distinct motifs for colonizing different host niches by adhesion: the β-helix/α-crystallin module of Awp1-related adhesins and the C-type lectin PA14-domain for Epa and Pwp proteins
Summary
The yeast Candida glabrata is an opportunistic human pathogen that can cause mucosal, bloodstream, and medical device-related infections [1,2]. As adhesion to host tissues or to medical devices is an important first step in the establishment of fungal infections, it is regarded as an important pathogenicity factor. The N-terminal region of mature GPI cell wall proteins (GPI-CWPs)– referred to as A-region–is believed to define the ligand-binding function. This region is followed by a low complexity region, the B-region, which is usually rich in serine and threonine residues, presenting abundant acceptor sites for O-glycosylation, and usually contains a variable number of large tandem repeats. By being linked with its processed C-terminus to cell wall β-1,6-glucans via the glycan remnant of the GPI anchor, the heavily glycosylated B-region can interact with other cell wall glycans and act as spacer molecule to present the A-region along the cell surface [1,6]
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