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: 9.67). 09/2011; 108(38):15775-9. DOI: 10.1073/pnas.1103496108
Source: PubMed


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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Available from: Paula Salgado
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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.
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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.
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    • "Among the adhesins, the Agglutinin-like sequence (Als) family includes cell wall-linked glycoproteins encoded at 8 loci [29], [30]. Each member of the Als family contain N-terminal Ig-like invasin domains (Ig) which define substrate specificity and a variable number of 36-amino acid tandem repeats (TR domain) that contribute to substrate binding [31]–[34]. There is a glycosylated serine-threonine–rich domain and a GPI anchor that covalently links the protein to the cell [35]. "
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    ABSTRACT: Many fungal cell adhesion proteins form functional amyloid patches on the surface of adhering cells. The Candida albicans Agglutinin-like sequence (Als) adhesins are exemplars for this phenomenon, and have amyloid forming sequences that are conserved between family members. The Als5p amyloid sequence mediates amyloid fibril formation and is critical for cell adhesion and biofilm formation, and is also present in the related adhesins Als1p and Als3p. We have developed a fluorescent peptide probe containing the conserved Als amyloid-forming sequence. This peptide bound specifically to yeast expressing Als5p, but not to cells lacking the adhesin. The probe bound to both yeast and hyphal forms of C. albicans. Δals1/Δals3 single and double deletion strains exhibited reduced fluorescence, indicating that probe binding required expression of these proteins. Additionally, the Als peptide specifically stained fungal cells in abscesses in autopsy sections. Counterstaining with calcofluor white showed colocalization with the amyloid peptide. In addition, fungi in autopsy sections derived from the gastrointestinal tract showed colocalization of the amyloid-specific dye thioflavin T and the fluorescent peptide. Collectively, our data demonstrate that we can exploit amyloid sequence specificity for detection of functional amyloids in situ.
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