Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans.

Division of Molecular Biosciences, Imperial College London, Exhibition Road, South Kensington SW7 2AZ, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2011; 108(38):15775-9. DOI: 10.1073/pnas.1103496108
Source: PubMed

ABSTRACT Candida albicans is the most prevalent fungal pathogen in humans and a major source of life-threatening nosocomial infections. The Als (agglutinin-like sequence) glycoproteins are an important virulence factor for this fungus and have been associated with binding of host-cell surface proteins and small peptides of random sequence, the formation of biofilms and amyloid fibers. High-resolution structures of N-terminal Als adhesins (NT-Als; up to 314 amino acids) show that ligand recognition relies on a motif capable of binding flexible C termini of peptides in extended conformation. Central to this mechanism is an invariant lysine that recognizes the C-terminal carboxylate of ligands at the end of a deep-binding cavity. In addition to several protein-peptide interactions, a network of water molecules runs parallel to one side of the ligand and contributes to the recognition of diverse peptide sequences. These data establish NT-Als adhesins as a separate family of peptide-binding proteins and an unexpected adhesion system for primary, widespread protein-protein interactions at the Candida/host-cell interface.

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    • "This adhesion is mediated by cell wall components that interact with the host cells. The cell wall of C. albicans contains different carbohydrates that come into contact with epithelial cells and facilitate cell–cell interconnections (Klotz et al. 2004; Salgado et al. 2011; Tsai et al. 2011). Between these carbohydrates, mannans are the main and the major antigenic component of the cell wall of yeast (Nelson et al. 1991; Tsai et al. 2011; Hardison and Brown 2012). "
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    ABSTRACT: We have previously described the structure and the ability of a dimeric analog of the antimicrobial peptide Aurein 1.2 to aggregate Candida albicans. In this study, circular dichroism and fluorescence spectroscopy data showed that this aggregation is related to the interaction between the peptide and mannans, the main component of yeast cell wall. In this context, we propose a model in which dimers interact with the polysaccharide leading to cells aggregation.
    Amino Acids 09/2014; 46(11). DOI:10.1007/s00726-014-1832-x · 3.65 Impact Factor
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    • "These Ig-fold domains bind to many different peptide sequences, either as soluble peptides or as unstructured parts of proteins [4] [5] [6]. The structures of these domains have now been determined [7]. Following the Ig-like domains is a Thr-rich domain of 108 amino acids, called the T domain. "
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    ABSTRACT: We tell of a journey that led to discovery of amyloids formed by yeast cell adhesins and their importance in biofilms and host immunity. We begin with the identification of the adhesin functional amyloid-forming sequences that mediate fiber formation in vitro. Atomic force microscopy and confocal microscopy show 2-dimensional amyloid "nanodomains" on the surface of cells that are activated for adhesion. These nanodomains are arrays of adhesin molecules that bind multivalent ligands with high avidity. Nanodomains form when adhesin molecules are stretched in the AFM or under laminar flow. Treatment with antiamyloid perturbants or mutation of the amyloid sequence prevents adhesion nanodomain formation and activation. We are now discovering biological consequences. Adhesin nanodomains promote formation and maintenance of biofilms, which are microbial communities. Also, in abscesses within candidiasis patients, we find adhesin amyloids on the surface of the fungi. In both human infection and a Caenorhabditis elegans infection model, the presence of fungal surface amyloids elicits anti-inflammatory responses. Thus, this is a story of how fungal adhesins respond to extension forces through formation of cell surface amyloid nanodomains, with key consequences for biofilm formation and host responses.
    02/2014; 2014:815102. DOI:10.1155/2014/815102
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    • "ALS genes have a similar organization. Each has a relatively conserved 5′ domain that encodes a peptide binding site (Salgado et al., 2011), a central domain that consists of head-to-tail copies of repeated sequence units, and a 3′ domain of relatively variable length and sequence. Mature Als proteins are glycosylated heavily and localized in the C. albicans cell wall. "
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    ABSTRACT: The Candida albicans agglutinin-like sequence (ALS) family encodes large cell surface glycoproteins that function in adhesion of the fungus to host and abiotic surfaces. Monoclonal antibodies (mAbs) specific for each Als protein were developed to study Als localization on the C. albicans surface. An anti-Als4 mAb demonstrated that Als4 covers the surface of yeast cells, with a greater abundance of Als4 on cells grown at 30 °C compared to 37 °C. On germ tubes, Als4 is localized in a restricted area proximal to the mother yeast. Immunolabeling with several anti-Als mAbs showed overlapping localization of Als1 and Als4 on yeast cells and Als1, Als3 and Als4 on germ tubes. Overlapping localization of Als proteins was also observed on yeast and hyphae recovered from mouse models of disseminated and oral candidiasis. Differences between Als localization in vivo and in vitro suggested changes in regulation of Als production in the host compared to the culture flask. Characterization with the anti-Als mAbs reveals the simultaneous presence and differences in relative abundance of Als proteins, creating an accurate image of Als representation and localization that can be used to guide conclusions regarding individual and collective Als protein function.
    FEMS Immunology & Medical Microbiology 11/2011; 64(3):321-33. DOI:10.1111/j.1574-695X.2011.00914.x · 2.55 Impact Factor
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